Kinases and phosphatases

ABSTRACT

The invention provides human kinases and phosphatases (KAP) and polnucleotides which identify and encode KAP. The invention also provides expresson vectors, host cells, antibodies, agonists, and antagonists. The invention also provides methods for diagnosing, treating, or preventing disorders associated with aberrant expression of KAP.

TECHNICAL FIELD

[0001] This invention relates to nucleic acid and amino acid sequences of kinases and phosphatases and to the use of these sequences in the diagnosis, treatment, and prevention of cardiovascular diseases, immune system disorders, neurological disorders, disorders affecting growth and development, lipid disorders, cell proliferative disorders, and cancers, and in the assessment of the effects of exogenous compounds on the expression of nucleic acid and amino acid sequences of kinases and phosphatases.

BACKGROUND OF THE INVENTION

[0002] Reversible protein phosphorylation is the ubiquitous strategy used to control many of the intracellular events in eukaryotic cells. It is estimated that more than ten percent of proteins active in a typical mammalian cell are phosphorylated. Kinases catalyze the transfer of high-energy phosphate groups from adenosine triphosphate (ATP) to target proteins on the hydroxyamino acid residues serine, threonine, or tyrosine. Phosphatases, in contrast, remove these phosphate groups. Extracellular signals including hormones, neurotransmitters, and growth and differentiation factors can activate kinases, which can occur as cell surface receptors or as the activator of the final effector protein, as well as other locations along the signal transduction pathway. Cascades of kinases occur, as well as kinases sensitive to second messenger molecules. This system allows for the amplification of weak signals (low abundance growth factor molecules, for example), as well as the synthesis of many weak signals into an all-or-nothing response. Phosphatases, then, are essential in determining the extent of phosphorylation in the cell and, together with kinases, regulate key cellular processes such as metabolic enzyme activity, proliferation, cell growth and differentiation, cell adhesion, and cell cycle progression.

Kinases

[0003] Kinases comprise the largest known enzyme superfamily and vary widely in their target molecules. Kinases catalyze the transfer of high energy phosphate groups from a: phosphate donor to a phosphate acceptor. Nucleotides usually serve as the phosphate donor in these reactions, with most kinases utilizing adenosine triphosphate (ATP). The phosphate acceptor can be any of a variety of molecules, including nucleosides, nucleotides, lipids, carbohydrates, and proteins. Proteins are phosphorylated on hydroxyamino acids. Addition of a phosphate group alters the local charge on the acceptor molecule, causing internal conformational changes and potentially influencing intermolecular contacts. Reversible protein phosphorylation is the primary method for regulating protein activity in eukaryotic cells. In general, proteins are activated by phosphorylation in response to extracellular signals such as hormones, neurotransmitters, and growth and differentiation factors. The activated proteins initiate the cell's intracellular response by way of intracellular signaling pathways and second messenger molecules such as cyclic nucleotides, calcium-calmodulin, inositol, and various mitogens, that regulate protein phosphorylation.

[0004] Kinases are involved in all aspects of a cell's function, from basic metabolic processes, such as glycolysis, to cell-cycle regulation, differentiation, and communication with the extracellular environment through signal transduction cascades. Inappropriate phosphorylation of proteins in cells has been linked to changes in cell cycle progression and cell differentiation. Changes in the cell cycle have been linked to induction of apoptosis or cancer. Changes in cell differentiation have been linked to diseases and disorders of the reproductive system, immune system, and skeletal muscle.

[0005] There are two classes of protein kinases. One class, protein tyrosine kinases (PTKs), phosphorylates tyrosine residues, and the other class, protein serine/threonine kinases (STKs), phosphorylates serine and threonine residues. Some PTKs and STKs possess structural characteristics of both families and have dual specificity for both tyrosine and serine/threonine residues. Almost all kinases contain a conserved 250-300 amino acid catalytic domain containing specific residues and sequence motifs characteristic of the kinase family. The protein kinase catalytic domain can be further divided into 11 subdomains. N-terminal subdomains I-IV fold into a two-lobed structure which binds and orients the ATP donor molecule, and subdomain V spans the two lobes. C-terminal subdomains VI-XI bind the protein substrate and transfer the gamma phosphate from ATP to the hydroxyl group of a tyrosine, serine, or threonine residue. Each of the 11 subdomains contains specific catalytic residues or amino acid motifs characteristic of that subdomain. For example, subdomain I contains an 8-amino acid glycine-rich ATP binding consensus motif, subdomain II contains a critical lysine residue required for maximal catalytic activity, and subdomains VI through IX comprise the highly conserved catalytic core. PTKs and STKs also contain distinct sequence motifs in subdomains VI and VIII which may confer hydroxyamino acid specificity.

[0006] In addition, kinases may also be classified by additional amino acid sequences, generally between 5 and 100 residues, which either flank or occur within the kinase domain. These additional amino acid sequences regulate kinase activity and determine substrate specificity. (Reviewed in Hardie, G. and S. Hanks (1995) The Protein Kinase Facts Book, Vol I, pp. 17-20 Academic Press, San Diego Calif.). In particular, two protein kinase signature sequences have been identified in the kinase domain, the first containing an active site lysine residue involved in ATP binding, and the second containing an aspartate residue important for catalytic activity. If a protein analyzed includes the two protein kinase signatures, the probability of that protein being a protein kinase is close to 100% (PROSITE: PDOC00100, November 1995).

Protein Tyrosine Kinases

[0007] Protein tyrosine kinases (PTKs) may be classified as either transmembrane, receptor PTKs or nontransmembrane, nonreceptor PTK proteins. Transmembrane tyrosine kinases function as receptors for most growth factors. Growth factors bind to the receptor tyrosine kinase (RTK), which causes the receptor to phosphorylate itself (autophosphorylation) and specific intracellular second messenger proteins. Growth factors (GF) that associate with receptor PTKs include epidermal GF, platelet-derived GP, fibroblast GF, hepatocyte GF, insulin and insulin-like GFs, nerve GF, vascular endothelial GF, and macrophage colony stimulating factor.

[0008] Nontransmembrane, nonreceptor PTKs lack transmembrane regions and, instead, form signaling complexes with the cytosolic domains of plasma membrane receptors. Receptors that function through non-receptor PTKs include those for cytokines and hormones (growth hormone and prolactin), and antigen-specific receptors on T and B lymphocytes.

[0009] Many PTKs were first identified as oncogene products in cancer cells in which PTK activation was no longer subject to normal cellular controls. In fact, about one third of the known oncogenes encode PIKS. Furthermore, cellular transformation (oncogenesis) is often accompanied by increased tyrosine phosphorylation activity (Charbonneau, H. and N. K. Tonks (1992) Annu. Rev. Cell Biol. 8:463-493). Regulation of PTK activity may therefore be an important strategy in controlling some types of cancer.

Protein Serine/Threonine Kinases

[0010] Protein serine/threonine kinases (STKs) are nontransmembrane proteins. A subclass of STKs are known as ERKs (extracellular signal regulated kinases) or MAPs (mitogen-activated protein kinases) and are activated after cell stimulation by a variety of hormones and growth factors. Cell stimulation induces a signaling cascade leading to phosphorylation of MEK (MAP/ERK kinase) which, in turn, activates ERK via serine and threonine phosphorylation. A varied number of proteins represent the downstream effectors for the active ERK and implicate it in the control of cell proliferation and differentiation, as well as regulation of the cytoskeleton. Activation of ERK is normally transient, and cells possess dual specificity phosphatases that are responsible for its down-regulation. Also, numerous studies have shown that elevated ERK activity is associated with some cancers. Other STKs include the second messenger dependent protein kinases such as the cyclic-AMP dependent protein kinases (PKA), calcium-calmodulin (CaM) dependent protein kinases, and the mitogen-activated protein kinases (MAP); the cyclin-dependent protein kinases; checkpoint and cell cycle kinases; Numb-associated kinase (Nak); human Fused (hFu); proliferation-related kinases; 5′-AMP-activated protein kinases; and kinases involved in apoptosis.

[0011] One member of the ERK family of MAP kinases, ERK 7, is a novel 61-kDa protein that has motif similarities to ERK1 and ERK2, but is not activated by extracellular stimuli as are ERK1 and ERK2 nor by the common activators, c-Jun N-terminal kinase (JNK) and p38 kinase. ERK7 regulates its nuclear localization and inhibition of growth through its C-terminal tail, not through the kinase domain as is typical with other MAP kinases (Abe, M. K. (1999) Mol. Cell. Biol. 19:1301-1312).

[0012] The second messenger dependent protein kinases primarily mediate the effects of second messengers such as cyclic AMP (cAMP), cyclic GMP, inositol triphosphate, phosphatidylinositol, 3,4,5-triphosphate, cyclic ADP ribose, arachidonic acid, diacylglycerol and calcium-calmodulin. The PKAs are involved in mediating hormone-induced cellular responses and are activated by cAMP produced within the cell in response to hormone stimulation. cAMP is an intracellular mediator of hormone action in all animal cells that have been studied. Hormone-induced cellular responses include thyroid hormone secretion, cortisol secretion, progesterone secretion, glycogen breakdown, bone resorption, and regulation of heart rate and force of heart muscle contraction. PKA is found in all animal cells and is thought to account for the effects of cAMP in most of these cells. Altered PKA expression is implicated in a variety of disorders and diseases including cancer, thyroid disorders, diabetes, atherosclerosis, and cardiovascular disease (Isselbacher, K. J. et al. (1994) Harrison's Principles of Internal Medicine, McGraw-Hill, New York N.Y., pp. 416-431, 1887).

[0013] The casein kinase I (CKI) gene family is another subfamily of serine/threonine protein kinases. This continuously expanding group of kinases have been implicated in the regulation of numerous cytoplasmic and nuclear processes, including cell metabolism and DNA replication, and repair. CKI enzymes are present in the membranes, nucleus, cytoplasm and cytoskeleton of eukaryotic cells, and on the mitotic spindles of mammalian cells (Fish, K. J. et al. (1995) J. Biol. Chem. 270:14875-14883).

[0014] The CKI family members all have a short amino-terminal domain of 9-76 amino acids, a highly conserved kinase domain of 284 amino acids, and a variable carboxyl-terminal domain that ranges from 24 to over 200 amino acids in length (Cegielska, A. et al. (1998) J. Biol. Chem. 273:1357-1364). The CKI family is comprised of highly related proteins, as seen by the identification of isoforms of casein kinase I from a variety of sources. There are at least five mammalian isoforms, α, β, γ, δ, and ε. Fish et al. identified CKI-epsilon from a human placenta cDNA library. It is a basic protein of 416 amino acids and is closest to CKI-delta. Through recombinant expression, it was determined to phosphorylate known CKI substrates and was inhibited by the CKI-specific inhibitor CKI-7. The human gene for CKI-epsilon was able to rescue yeast with a slow-growth phenotype caused by deletion of the yeast CKI locus, HRR250 (Fish et al., supra).

[0015] The mammalian circadian mutation tau was found to be a semidominant autosomal allele of CKI-epsilon that markedly shortens period length of circadian rhythms in Syrian hamsters. The tau locus is encoded by casein kinase I-epsilon, which is also a homolog of the Drosophila circadian gene double-time. Studies of both the wildtype and tau mutant CKI-epsilon enzyme indicated that the mutant enzyme has a noticeable reduction in the maximum velocity and autophosphorylation state. Further, in vitro, CKI-epsilon is able to interact with mammalian PERIOD proteins, while the mutant enzyme is deficient in its ability to phosphorylate PERIOD. Lowrey et al. have proposed that CKI-epsilon plays a major role in delaying the negative feedback signal within the tnanscription-translation-based autoregulatory loop that composes the core of the circadian mechanism Therefore the CKI-epsilon enzyme is an ideal target for pharmaceutical compounds influencing circadian rhythms, jet-lag and sleep, in addition to other physiologic and metabolic processes under circadian regulation (Lowrey, P. L. et al. (2000) Science 288:483-491).

Calcium-Calmodulin Dependent Protein Kinases

[0016] Calcium-calmodulin dependent (CaM) kinases are involved in regulation of smooth muscle contraction, glycogen breakdown (phosphorylase kinase), and neurotransmission (CaM kinase I and CaM kinase II). CaM dependent protein kinases are activated by calmodulin, an intracellular calcium receptor, in response to the concentration of free calcium in the cell. Many CaM kinases are also activated by phosphorylation. Some CaM kinases are also activated by autophosphorylation or by other regulatory kinases. CaM kinase I phosphorylates a variety of substrates including the neurotransmitter-related proteins synapsin I and II, the gene transcription regulator, CREB, and the cystic fibrosis conductance regulator protein, CFTR (Haribabu, B. et al. (1995) EMBO J. 14:3679-3686). CaM kinase II also phosphorylates synapsin at different sites and controls the synthesis of catecholamines in the brain through phosphorylation and activation of tyrosine hydroxylase. CaM kinase II controls the synthesis of catecholamines and seratonin, through phosphorylation/activation of tyrosine hydroxylase and tryptophan hydroxylase, respectively (Fujisawa, H. (1990) BioEssays 12:27-29). The mRNA encoding a calmodulin-binding protein kinase-like protein was found to be enriched in mammalian forebrain. This protein is associated with vesicles in both axons and dendrites and accumulates largely postnatally. The amino acid sequence of this protein is similar to CaM-dependent STKs, and the protein binds calmodulin in the presence of calcium (Godbout, M. et al. (1994) J. Neurosci. 14:1-13).

[0017] Homeodomain-interacting protein kinases (HIPKs) are serine/threonine kinases and novel members of the DYRK kinase subfamily (Hofmann, T. G. et al. (2000) Biochimie 82:1123-1127). HIPKs contain a conserved protein kinase domain separated from a domain that interacts with homeoproteins. HIPKs are nuclear kinases, and HIPK2 is highly expressed in neuronal tissue (Kim, Y. H. et al. (1998) J. Biol. Chem. 273:25875-25879; Wang, Y. et al. (2001) Biochim. Biophys. Acta 1518:168-172). HIPKs act as corepressors for homeodomian transcription factors. This corepressor activity is seen in posttranslational modifications such as ubiquitination and phosphorylation, each of which are important in the regulation of cellular protein function (Kim, Y. H. et al. (1999) Proc. Natl. Acad. Sci. USA 96:12350-12355).

[0018] The human h-warts protein, a homolog of Drosophila warts tumor suppressor gene, maps to chromosome 6q24-25.1. It has a serine/threonine kinase domain and is localized to centrosomes in interphase cells. It is involved in mitosis and functions as a component of the mitotic apparatus (Nishiyama, Y. et al. (1999) FEBS Lett. 459:159-165).

Calcium-Calmodulin Dependent Protein Kinases

[0019] Calcium-calmodulin dependent (CaM) kinases are involved in regulation of smooth muscle contraction, glycogen breakdown (phosphorylase kinase), and neurotransmission (CaM kinase I and CaM kinase II). CaM dependent protein kinases are activated by calmodulin, an intracellular calcium receptor, in response to the concentration of free calcium in the cell. Many CaM kinases are also activated by phosphorylation. Some CaM kinases are also activated by autophosphorylation or by other regulatory kinases. CaM kinase I phosphorylates a variety of substrates including the neurotransmitter-related proteins synapsin I and II, the gene transcription regulator, CREB, and the cystic fibrosis conductance regulator protein, CFTR (Haribabu, B. et al. (1995) EMBO J. 14:3679-3686). CaM kinase II also phosphorylates synapsin at different sites and controls the synthesis of catecholamines in the brain through phosphorylation and activation of tyrosine hydroxylase. CaM kinase II controls the synthesis of catecholamines and seratonin, through phosphorylation/activation of tyrosine hydroxylase and tryptophan hydroxylase, respectively (Fujisawa, H. (1990) BioEssays 12:27-29). The mRNA encoding a calmodulin-binding protein kinase-like protein was found to be enriched in mammalian forebrain. This protein is associated with vesicles in both axons and dendrites and accumulates largely postnatally. The amino acid sequence of this protein is similar to CaM-dependent STKs, and the protein binds calmodulin in the presence of calcium (Godbout, M. et al. (1994) J. Neurosci. 14:1-13).

Mitogen-Activated Protein Kinases

[0020] The mitogen-activated protein kinases (MAP), which mediate signal transduction from the cell surface to the nucleus via phosphorylation cascades, are another STK family that regulates intracellular signaling pathways. Several subgroups have been identified, and each manifests different substrate specificities and responds to distinct extracellular stimuli (Egan, S. E. and R. A. Weinberg (1993) Nature 365:781-783). There are three kinase modules comprising the MAP kinase cascade: MAPK (MAP), MAPK kinase (MAP2K, MAPKK, or MKK), and MKK kinase (MAP3K, MAPKKK, OR MEKK) (Wang, X. S. et al (1998) Biochem. Biophys. Res. Commun. 253:33-37). The extracellular-regulated kinase (ERK) pathway is activated by growth factors and mitogens, for example, epidermal growth factor (EGF), ultraviolet light, hyperosmolar medium, heat shock, or endotoxic lipopolysaccharide (LPS). The closely related though distinct parallel pathways, the c-Jun N-terminal kinase (JNK), or stress-activated kinase (SAPK) pathway, and the p38 kinase pathway are activated by stress stimuli and proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1). Altered MAP kinase expression is implicated in a variety of disease conditions including cancer, inflammation, immune disorders, and disorders affecting growth and development. MAP kinase signaling pathways are present in mammalian cells as well as in yeast.

[0021] The family of p21-activated protein kinases (PAKs) appear to be present in all organisms that have Cdc42-like GTPases. In mammalian cells, PAKs have been implicated in the activation of mitogen-activated protein kinase cascades. PAK functions also include the dissolution of cytoskeletal stress fibers and reorganization of focal complexes (Manser, E. et al. (1997) Mol. Cell Biol. 17(3):1129-1143).

Cyclin-Dependent Protein Kinases

[0022] The cyclin-dependent protein kinases (CDKs) are STKs that control the progression of cells through the cell cycle. The entry and exit of a cell from mitosis are regulated by the synthesis and destruction of a family of activating proteins called cyclins. Cyclins are small regulatory proteins that bind to and activate CDKs, which then phosphorylate and activate selected proteins involved in the mitotic process. CDKs are unique in that they require multiple inputs to become activated. In addition to cyclin binding, CDK activation requires the phosphorylation of a specific threonine residue and the dephosphorylation of a specific tyrosine residue on the CDK.

[0023] Another family of STKs associated with the cell cycle are the NIMA (never in mitosis)-related kinases (Neks). Both CDKs and Neks are involved in duplication, maturation, and separation of the microtubule organizing center, the centrosome, in animal cells (Fry, A. M. et al. (1998) EMBO J. 17:470-481).

Checkpoint and Cell Cycle Kinases

[0024] In the process of cell division, the order and timing of cell cycle transitions are under control of cell cycle checkpoints, which ensure that critical events such as DNA replication and chromosome segregation are carried out with precision. If DNA is damaged, e.g. by radiation, a checkpoint pathway is activated that arrests the cell cycle to provide time for repair. If the damage is extensive, apoptosis is induced. In the absence of such checkpoints, the damaged DNA is inherited by aberrant cells which may cause proliferative disorders such as cancer. Protein kinases play an important role in this process. For example, a specific kinase, checkpoint kinase 1 (Chk1), has been identified in yeast and mammals, and is activated by DNA damage in yeast. Activation of Chk1 leads to the arrest of the cell at the G2/M transition (Sanchez, Y. et al. (1997) Science 277:1497-1501). Specifically, Chk1 phosphorylates the cell division cycle phosphatase CDC25, inhibiting its normal function which is to dephosphorylate and activate the cyclin-dependent kinase Cdc2. Cdc2 activation controls the entry of cells into mitosis (Peng, C. -Y. et al. (1997) Science 277:1501-1505). Thus, activation of Chk1 prevents the damaged cell from entering mitosis. A deficiency in a checkpoint kinase, such as Chk1, may also contribute to cancer by failure to arrest cells with damaged DNA at other checkpoints such as G2/M.

Proliferation-Related Kinases

[0025] Proliferation-related kinase is a serum/cytokine inducible STK that is involved in regulation of the cell cycle and cell proliferation in human megakarocytic cells (Li, B. et al. (1996) J. Biol. Chem 271:19402-19408). Proliferation-related kinase is related to the polo (derived from Drosophila polo gene) family of STKs implicated in cell division. Proliferation-related kinase is downregulated in lung tumor tissue and may be a proto-oncogene whose deregulated expression in normal tissue leads to oncogenic transformation.

5′-AMP-Activated Protein Kinase

[0026] A ligand-activated STK protein kinase is 5′-AMP-activated protein kinase (AMPK) (Gao, G. et al. (1996) J. Biol Chem. 271:8675-8681). Mammalian AMPK is a regulator of fatty acid and sterol synthesis through phosphorylation of the enzymes acetyl-CoA carboxylase and hydroxymethylglutaryl-CoA reductase and mediates responses of these pathways to cellular stresses such as heat shock and depletion of glucose and ATP. AMPK is a heterotrimeric complex comprised of a catalytic alpha subunit and two non-catalytic beta and gamma subunits that are believed to regulate the activity of the alpha subunit. Subunits of AMPK have a much wider distribution in non-lipogenic tissues such as brain, heart, spleen, and lung than expected. This distribution suggests that its role may extend beyond regulation of lipid metabolism alone.

[0027] The RET (rearranged during transfection) proto-oncogene encodes a tyrosine kinase receptor involved in both multiple endocrine neoplasia type 2, an inherited cancer syndrome, and Hirschsprung disease, a developmental defect of enteric neurons. RET and its functional ligand, glial cell line-derived neurotrophic factor, play key roles in the development of the human enteric nervous system (Pachnis, V. et al. (1998) Am. J. Physiol. 275:G183-G186).

Kinases in Apoptosis

[0028] Apoptosis is a highly regulated signaling pathway leading to cell death that plays a crucial role in tissue development and homeostasis. Deregulation of this process is associated with the pathogenesis of a number of diseases including autoimmune diseases, neurodegenerative disorders, and cancer. Various STXs play key roles in this process. ZIP kinase is an STK containing a C-terminal leucine zipper domain in addition to its N-terminal protein kinase domain. This C-terminal domain appears to mediate homodimerization and activation of the kinase as well as interactions with transcription factors such as activating transcription factor, ATF4, a member of the cyclic-AMP responsive element binding protein (ATF/CREB) family of transcriptional factors (Sanjo, H. et al. (1998) J. Biol. Chem. 273:29066-29071). DRAK1 and DRAK2 are STKs that share homology with the death-associated protein kinases (DAP kinases), known to function in interferon-γ induced apoptosis (Sanjo et al., supra). Like ZIP kinase, DAP kinases contain a C-terminal protein-protein interaction domain, in the form of ankyrin repeats, in addition to the N-terminal kinase domain. ZIP, DAP, and DRAK kinases induce morphological changes associated with apoptosis when transfected into NIH3T3 cells (Sanjo et al., supra). However, deletion of either the N-terminal kinase catalytic domain or the C-terminal domain of these proteins abolishes apoptosis activity, indicating that in addition to the kinase activity, activity in the C-terminal domain is also necessary for apoptosis, possibly as an interacting domain with a regulator or a specific substrate.

[0029] RICK is another STK recently identified as mediating a specific apoptotic pathway involving the death receptor, CD95 (Inohara, N. et al. (1998) J. Biol. Chem 273:12296-12300). CD95 is a member of the tumor necrosis factor receptor superfamily and plays a critical role in the regulation and homeostasis of the immune system (Nagata, S. (1997) Cell 88:355-365). The CD95 receptor signaling pathway involves recruitment of various intracellular molecules to a receptor complex following ligand binding. This process includes recruitment of the cysteine protease caspase-8 which, in turn, activates a caspase cascade leading to cell death. RICK is composed of an N-terminal kinase catalytic domain and a C-terminal “caspase-recruitment” domain that interacts with caspase-like domains, indicating that RICK plays a role in the recruitment of caspase-8. This interpretation is supported by the fact that the expression of RICK in human 293T cells promotes activation of caspase-8 and potentiates the induction of apoptosis by various proteins involved in the CD95 apoptosis pathway (Inohara et al., supra).

Mitochondrial Protein Kinases

[0030] A novel class of eukaryotic kinases, related by sequence to prokaryotic histidine protein kinases, are the mitochondrial protein kinases (MPKs) which seem to have no sequence similarity with other eukaryotic protein kinases. These protein kinases are located exclusively in the mitochondrial matrix space and may have evolved from genes originally present in respiration-dependent bacteria which were endocytosed by primitive eukaryotic cells. MPKs are responsible for phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase and pyruvate dehydrogenase complexes (Harris, R. A. et al. (1995) Adv. Enzyme Regul. 34:147-162). Five MPKs have been identified. Four members correspond to pyruvate dehydrogenase kinase isozymes, regulating the activity of the pyruvate dehydrogenase complex, which is an important regulatory enzyme at the interface between glycolysis and the citric acid cycle. The fifth member corresponds to a branched-chain alpha-ketoacid dehydrogenase kinase, important in the regulation of the pathway for the disposal of branched-chain amino acids. (Harris, R. A. et al. (1997) Adv. Enzyme Regul. 37:271-293). Both starvation and the diabetic state are known to result in a great increase in the activity of the pyruvate dehydrogenase kinase in the liver, heart and muscle of the rat. This increase contributes in both disease states to the phosphorylation and inactivation of the pyruvate dehydrogenase complex and conservation of pyruvate and lactate for gluconeogenesis (Harris (1995) supra).

Kinases with Non-Protein Substrates Lipid and Inositol Kinases

[0031] Lipid kinases phosphorylate hydroxyl residues on lipid head groups. A family of kinases involved in phosphorylation of phosphatidylinositol (PI) has been described, each member phosphorylating a specific carbon on the inositol ring (Leevers, S. J. et al. (1999) Curr. Opin. Cell. Biol. 11:219-225). The phosphorylation of phosphatidylinositol is involved in activation of the protein kinase C signaling pathway. The inositol phospholipids (phosphoinositides) intracellular signaling pathway begins with binding of a signaling molecule to a G-protein linked receptor in the plasma membrane. This leads to the phosphorylation of phosphatidylinositol (PI) residues on the inner side of the plasma membrane by inositol kinases, thus converting PI residues to the biphosphate state (PIP₂). PIP₂ is then cleaved into inositol triphosphate (IP₃) and diacylglycerol. These two products act as mediators for separate signaling pathways. Cellular responses that are mediated by these pathways are glycogen breakdown in the liver in response to vasopressin, smooth muscle contraction in response to acetylcholine, and thrombin-induced platelet aggregation.

[0032] PI 3-kinase (PI3K), which phosphorylates the D3 position of PI and its derivatives, has a central role in growth factor signal cascades involved in cell growth, differentiation, and metabolism PI3K is a heterodimer consisting of an adapter subunit and a catalytic subunit. The adapter subunit acts as a scaffolding protein, interacting with specific tyrosine-phosphorylated proteins, lipid moieties, and other cytosolic factors. When the adapter subunit binds tyrosine phosphorylated targets, such as the insulin responsive substrate (IRS)-1, the catalytic subunit is activated and converts PI (4,5) bisphosphate (PIP₂) to PI (3,4,5) P₃ (PIP₃). PIP₃ then activates a number of other proteins, including PKA, protein kinase B (PKB), protein kinase C (PKC), glycogen synthase kinase (GSK)-3, and p70 ribosomal s6 kinase. PI3K also interacts directly with the cytoskeletal organizing proteins, Rac, rho, and cdc42 (Shepherd, P. R. et al. (1998) Biochem. J. 333:471-490). Animal models for diabetes, such as obese and fat mice, have altered PI3K adapter subunit levels. Specific mutations in the adapter subunit have also been found in an insulin-resistant Danish population, suggesting a role for PI3K in type-2 diabetes (Shepard, supra).

[0033] An example of lipid kinase phosphorylation activity is the phosphorylation of D-erythro-sphingosine to the sphingolipid metabolite, sphingosine-1-phosphate (SPP). SPP has emerged as a novel lipid second-messenger with both extracellular and intracellular actions (Kohama, T. et al. (1998) J. Biol. Chem 273:23722-23728). Extracellularly, SPP is a ligand for the G-protein coupled receptor EDG-1 (endothelial-derived, G-protein coupled receptor). Intracellularly, SPP regulates cell growth, survival, motility, and cytoskeletal changes. SPP levels are regulated by sphingosine kinases that specifically phosphorylate D-erythro-sphingosine to SPP. The importance of sphingosine kinase in cell signaling is indicated by the fact that various stimuli, including platelet-derived growth factor (PDGF), nerve growth factor, and activation of protein kinase C, increase cellular levels of SPP by activation of sphingosine kinase, and the fact that competitive inhibitors of the enzyme selectively inhibit cell proliferation induced by PDGF (Kohama et al., supra).

[0034] PKC is also activated by diacylglycerol (DAG). Phorbol esters (PE) are analogs of DAG and tumor promoters that cause a variety of physiological changes when administered to cells and tissues. PE and DAG bind to the N-terminal region of PKC. This region contains one or more copies of a cysteine-rich domain about 50 amino-acid residues long and essential for DAG/PE-binding. Diacylglycerol kinase (DGK), the enzyme that converts DAG into phosphatidate, contains two copies of the DAG/PE-binding domain in its N-terminal section (Azzi, A. et al. (1992) Eur. J. Biochem. 208:547-557).

[0035] An example of lipid kinase phosphorylation activity is the phosphorylation of D-erythro-sphingosine to the sphingolipid metabolite, sphingosine-1-phosphate (SPP). SPP has emerged as a novel lipid second-messenger with both extracellular and intracellular actions (Kohama, T. et al. (1998) J. Biol. Chem 273:23722-23728). Extracellularly, SPP is a ligand for the G-protein coupled receptor EDG-1 (endothelial-derived, G-protein coupled receptor). Intracellularly, SPP regulates cell growth, survival, motility, and cytoskeletal changes. SPP levels are regulated by sphingosine kinases that specifically phosphorylate D-erythro-sphingosine to SPP. The importance of sphingosine kinase in cell signaling is indicated by the fact that various stimuli, including platelet-derived growth factor (PDGF), nerve growth factor, and activation of protein kinase C, increase cellular levels of SPP by activation of sphingosine kinase, and the fact that competitive inhibitors of the enzyme selectively inhibit cell proliferation induced by PDGF (Kohama et al. supra).

Purine Nucleotide Kinases

[0036] The purine nucleotide kinases, adenylate kinase (ATP:AMP phosphotransferase, or AdK) and guanylate kinase (ATP:GMP phosphotransferase, or GuK) play a key role in nucleotide metabolism and are crucial to the synthesis and regulation of cellular levels of ATP and GTP, respectively. These two molecules are precursors in DNA and RNA synthesis in growing cells and provide the primary source of biochemical energy in cells (ATP), and signal transduction pathways (GTP). Inhibition of various steps in the synthesis of these two molecules has been the basis of many antiproliferative drugs for cancer and antiviral therapy (Pillwein, K. et al. (1990) Cancer Res. 50:1576-1579).

[0037] AdK is found in almost all cell types and is especially abundant in cells having high rates of ATP synthesis and utilization such as skeletal muscle. In these cells AdK is physically associated with mitochondria and myofibrils, the subcellular structures that are involved in energy production and utilization, respectively. Recent studies have demonstrated a major function for AdK in transferring high energy phosphoryls from metabolic processes generating ATP to cellular components consuming ATP (Zeleznikar, R. J. et al. (1995) J. Biol. Chem. 270:7311-7319). Thus AdK may have a pivotal role in maintaining energy production in cells, particularly those having a high rate of growth or metabolism such as cancer cells, and may provide a target for suppression of its activity in order to treat certain cancers. Alternatively, reduced AdK activity may be a source of various metabolic, muscle-energy disorders that can result in cardiac or respiratory failure and may be treatable by increasing AdK activity.

[0038] GuK, in addition to providing a key step in the synthesis of GTP for RNA and DNA synthesis, also fulfills an essential function in signal transduction pathways of cells through the regulation of GDP and GTP. Specifically, GTP binding to membrane associated G proteins mediates the activation of cell receptors, subsequent intracellular activation of adenyl cyclase, and production of the second messenger, cyclic AMP. GDP binding to G proteins inhibits these processes. GDP and GTP levels also control the activity of certain oncogenic proteins such as p21^(ras) known to be involved in control of cell proliferation and oncogenesis (Bos, J. L. (1989) Cancer Res. 49:4682-4689). High ratios of GTP:GDP caused by suppression of GuK cause activation of p21^(ras) and promote oncogenesis. Increasing GuK activity to increase levels of GDP and reduce the GTP:GDP ratio may provide a therapeutic strategy to reverse oncogenesis.

[0039] GuK is an important enzyme in the phosphorylation and activation of certain antiviral drugs useful in the treatment of herpes virus infections. These drugs include the guanine homologs acyclovir and buciclovir (Miller, W. H. and R. L. Miller (1980) J. Biol. Chem. 255:7204-7207; Stenberg, K. et al. (1986) J. Biol. Chem. 261:2134-2139). Increasing GuK activity in infected cells may provide a therapeutic strategy for augmenting the effectiveness of these drugs and possibly for reducing the necessary dosages of the drugs.

Pyrimidine Kinases

[0040] The pyrimidine kinases are deoxycytidine kinase and thymidine kinase 1 and 2. Deoxycytidine kinase is located in the nucleus, and thymidine kinase 1 and 2 are found in the cytosol (Johansson, M. et al. (1997) Proc. Natl. Acad. Sci. USA 94:11941-11945). Phosphorylation of deoxyribonucleosides by pyrimidine kinases provides an alternative pathway for de novo synthesis of DNA precursors. The role of pyrimidine kinases, like purine kinases, in phosphorylation is critical to the activation of several chemotherapeutically important nucleoside analogues (Armer E. S. and S. Eriksson (1995) Pharmacol. Ther. 67:155-186).

Phosphatases

[0041] Protein phosphatases are generally characterized as either serine/threonine- or tyrosine-specific based on their preferred phospho-amino acid substrate. However, some phosphatases (DSPs, for dual specificity phosphatases) can act on phosphorylated tyrosine, serine, or threonine residues. The protein serine/threonine phosphatases (PSPs) are important regulators of many cAMP-mediated hormone responses in cells. Protein tyrosine phosphatases (PTPs) play a significant role in cell cycle and cell signaling processes. Another family of phosphatases is the acid phosphatase or histidine acid phosphatase (HAP) family whose members hydrolyze phosphate esters at acidic pH conditions.

[0042] PSPs are found in the cytosol, nucleus, and mitochondria and in association with cytoskeletal and membranous structures in most tissues, especially the brain. Some PSPs require divalent cations, such as Ca²⁺ or Mn²⁺, for activity. PSPs play important roles in glycogen metabolism, muscle contraction, protein synthesis, T cell function, neuronal activity, oocyte maturation, and hepatic metabolism (reviewed in Cohen, P. (1989) Annu. Rev. Biochem. 58:453-508). PSPs can be separated into two classes. The PPP class includes PP1, PP2A, PP2B/calcineurin, PP4, PP5, PP6, and PP7. Members of this class are composed of a homologous catalytic subunit bearing a very highly conserved signature sequence, coupled with one or more regulatory subunits (PROSITE PDOC00115). Further interactions with scaffold and anchoring molecules determine the intracellular localization of PSPs and substrate specificity. The PPM class consists of several closely related isoforms of PP2C and is evolutionarily unrelated to the PPP class.

[0043] PP1 dephosphorylates many of the proteins phosphorylated by cyclic AMP-dependent protein kinase (PKA) and is an important regulator of many cAMP-mediated hormone responses in cells. A number of isoforms have been identified, with the alpha and beta forms being produced by alternative splicing of the same gene. Both ubiquitous and tissue-specific targeting proteins for PP1 have been identified. In the brain, inhibition of PP1 activity by the dopamine and adenosine 3′,5′-monophosphate-regulated phosphoprotein of 32 kDa (DARPP-32) is necessary for normal dopamine response in neostriatal neurons (reviewed in Price, N. E. and M. C. Mumby (1999) Curr. Opin. Neurobiol. 9:336-342). PP1, along with PP2A, has been shown to limit motility in microvascular endothelial cells, suggesting a role for PSPs in the inhibition of angiogenesis (Gabel, S. et al. (1999) Otolaryngol. Head Neck Surg. 121:463-468).

[0044] PP2A is the main serine/threonine phosphatase. The core PP2A enzyme consists of a single 36 kDa catalytic subunit (C) associated with a 65 kDa scaffold subunit (A), whose role is to recruit additional regulatory subunits (B). Three gene families encoding B subunits are known (PR55, PR61, and PR72), each of which contain multiple isoforms, and additional families may exist (Millward, T. A et al. (1999) Trends Biosci. 24:186-191). These “B-type” subunits are cell type- and tissue-specific and determine the substrate specificity, enzymatic activity, and subcellular localization of the holoenzyme. The PR55 family is highly conserved and bears a conserved motif (PROSITE PDOC00785). PR55 increases PP2A activity toward mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK). PP2A dephosphorylates the MAPK active site, inhibiting the cell's entry into mitosis. Several proteins can compete with PR55 for PP2A core enzyme binding, including the CKII kinase catalytic subunit, polyomavirus middle and small T antigens, and SV40 small t antigen. Viruses may use this mechanism to commandeer PP2A and stimulate progression of the cell through the cell cycle (Pallas, D. C. et al. (1992) J. Virol. 66:886-893). Altered MAP kinase expression is also implicated in a variety of disease conditions including cancer, inflammation, immune disorders, and disorders affecting growth and development. PP2A, in fact, can dephosphorylate and modulate the activities of more than 30 protein kinases in vitro, and other evidence suggests that the same is true in vivo for such kinases as PKB, PKC, the calmodulin-dependent kinases, ERK family MAP kinases, cyclin-dependent kinases, and the IκK kinases (reviewed in Millward et al., supra. PP2A is itself a substrate for CKI and CKII kinases, and can be stimulated by polycationic macromolecules. A PP2A-like phosphatase is necessary to maintain the G1 phase destruction of mammalian cyclins A and B (Bastians, H. et al. (1999) Mol. Biol. Cell 10:3927-3941). PP2A is a major activity in the brain and is implicated in regulating neurofilament stability and normal neural function, particularly the phosphorylation of the microtubule-associated protein tau. Hyperphosphorylation of tau has been proposed to lead to the neuronal degeneration seen in Alzheimer's disease (reviewed in Price and Mumby, supra).

[0045] PP2B, or calcineurin, is a Ca²⁺-activated dimeric phosphatase and is particularly abundant in the brain. It consists of catalytic and regulatory subunits, and is activated by the binding of the calcium/calmodulin complex. Calcineurin is the target of the immunosuppressant drugs cyclosporine and FK506. Along with other cellular factors, these drugs interact with calcineurin and inhibit phosphatase activity. In T cells, this blocks the calcium dependent activation of the NF-AT family of transcription factors, leading to immunosuppression. This family is widely distributed, and it is likely that calcineurin regulates gene expression in other tissues as well. In neurons, calcineurin modulates functions which range from the inhibition of neurotransmitter release to desensitization of postsynaptic NMDA-receptor coupled calcium channels to long term memory (reviewed in Price and Mumby, supra).

[0046] Other members of the PPP class have recently been identified (Cohen, P. T. (1997) Trends Biochem. Sci. 22:245-251). One of them, PP5, contains regulatory domains with tetratricopeptide repeats. It can be activated by polyunsaturated fatty acids and anionic phospholipids in vitro and appears to be involved in a number of signaling pathways, including those controlled by atrial natriuretic peptide or steroid hormones (reviewed in Andreeva, A. V. and M. A. Kutuzov (1999) Cell Signal. 11:555-562).

[0047] PP2C is a ˜42kDa monomer with broad substrate specificity and is dependent on divalent cations (mainly Mn²⁺ or Mg²⁺) for its activity. PP2C proteins share a conserved N-terminal region with an invariant DGH motif, which contains an aspartate residue involved in cation binding (PROSITE PDOC00792). Targeting proteins and mechanisms regulating PP2C activity have not been identified. PP2C has been shown to inhibit the stress-responsive p38 and Jun kinase (JNK) pathways (Takekawa, M. et al. (1998) EMBO J. 17:4744-4752).

[0048] In contrast to PSPs, tyrosine-specific phosphatases (PTPs) are generally monomeric proteins of very diverse size (from 20 kDa to greater than 100 kDa) and structure that function primarily in the transduction of signals across the plasma membrane. PTPs are categorized as either soluble phosphatases or transmembrane receptor proteins that contain a phosphatase domain. All PTPs share a conserved catalytic domain of about 300 amino acids which contains the active site. The active site consensus sequence includes a cysteine residue which executes a nucleophilic attack on the phosphate moiety during catalysis (Neel, B. G. and N. K. Tonks (1997) Curr. Opin. Cell Biol. 9:193-204). Receptor PTPs are made up of an N-terminal extracellular domain of variable length, a transmembrane region, and a cytoplasmic region that generally contains two copies of the catalytic domain. Although only the first copy seems to have enzymatic activity, the second copy apparently affects the substrate specificity of the first. The extracellular domains of some receptor PTPs contain fibronectin-like repeats, immunoglobulin-like domains, MAM domains (an extracellular motif likely to have an adhesive function), or carbonic anhydrase-like domains (PROSITE PDOC 00323). This wide variety of structural motifs accounts for the diversity in size and specificity of PTPs.

[0049] PTPs play important roles in biological processes such as cell adhesion, lymphocyte activation, and cell proliferation. PTPs μ and κ are involved in cell-cell contacts, perhaps regulating cadherin/catenin function. A number of PTPs affect cell spreading, focal adhesions, and cell motility, most of them via the integrin/tyrosine kinase signaling pathway (reviewed in Neel and Tonks, supra). CD45 phosphatases regulate signal transduction and lymphocyte activation (Ledbetter, J. A. et al. (1988) Proc. Natl. Acad. Sci. USA 85:8628-8632). Soluble PTPs containing Src-homology-2 domains have been identified (SHPs), suggesting that these molecules might interact with receptor tyrosine kinases. SHP-1 regulates cytokine receptor signaling by controlling the Janus family PTKs in hematopoietic cells, as well as signaling by the T-cell receptor and c-Kit (reviewed in Neel and Tonks, supra). M-phase inducer phosphatase plays a key role in the induction of mitosis by dephosphorylating and activating the PTK CDC2, leading to cell division (Sadhu, K. et al. (1990) Proc. Natl. Acad. Sci. USA 87:5139-5143). In addition, the genes encoding at least eight PTPs have been mapped to chromosomal regions that are translocated or rearranged in various neoplastic conditions, including lymphoma, small cell lung carcinoma, leukemia, adenocarcinoma, and neuroblastoma (reviewed in Charbonneau, IL and N. K. Tonks (1992) Annu. Rev. Cell Biol. 8:463-493). The PTP enzyme active site comprises the consensus sequence of the MTM1 gene family. The MTM1 gene is responsible for X-linked recessive myotubular myopathy, a congenital muscle disorder that has been linked to Xq28 (Kioschis, P. et al., (1998) Genomics 54:256-266). Many PTKs are encoded by oncogenes, and it is well known that oncogenesis is often accompanied by increased tyrosine phosphorylation activity. It is therefore possible that PTPs may serve to prevent or reverse cell transformation and the growth of various cancers by controlling the levels of tyrosine phosphorylation in cells. This is supported by studies showing that overexpression of PTP can suppress transformation in cells and that specific inhibition of PIP can enhance cell transformation (Charbonneau and Tonks, supra).

[0050] Dual specificity phosphatases (DSPs) are structurally more similar to the PTPs than the PSPs. DSPs bear an extended PTP active site motif with an additional 7 amino acid residues. DSPs are primarily associated with cell proliferation and include the cell cycle regulators cdc25A, B, and C. The phosphatases DUSP1 and DUSP2 inactivate the MAPK family members ERK (extracellular signal-regulated kinase), JUNK (c-Jun N-terminal kinase), and p38 on both tyrosine and threonine residues (PROSITE PDOC 00323, supra). In the activated state, these kinases have been implicated in neuronal differentiation, proliferation, oncogenic transformation, platelet aggregation, and apoptosis. Thus, DSPs are necessary for proper regulation of these processes (Muda, M. et al. (1996) J. Biol. Chem 271:27205-27208). The tumor suppressor PTEN is a DSP that also shows lipid phosphatase activity. It seems to negatively regulate interactions with the extracellular matrix and maintains sensitivity to apoptosis. PTEN has been implicated in the prevention of angiogenesis (Giri, D. and M. Ittmann (1999) Hum. Pathol. 30:419-424) and abnormalities in its expression are associated with numerous cancers (reviewed in Tamura, M. et al. (1999) J. Natl. Cancer Inst. 91:1820-1828).

[0051] Histidine acid phosphatase (HAP; EXPASY EC 3.1.3.2), also known as acid phosphatase, hydrolyzes a wide spectrum of substrates including alkyl, aryl, and acyl orthophosphate monoesters and phosphorylated proteins at low pH. HAPs share two regions of conserved sequences, each centered around a histidine residue which is involved in catalytic activity. Members of the HAP family include lysosomal acid phosphatase (LAP) and prostatic acid phosphatase (PAP), both sensitive to inhibition by L-tartrate (PROSITE PDOC00538).

[0052] LAP, an orthophosphoric monoester of the endosomal/lysosomal compartment is a housekeeping gene whose enzymatic activity has been detected in all tissues examined (Geier, C. et al. (1989) Eur. J. Biochem. 183:611-616). LAP-deficient mice have progressive skeletal disorder and an increased disposition toward generalized seizures (Saftig, P. et al. (1997) J. Biol. Chem. 272:18628-18635). LAP-deficient patients were found to have the following clinical features: intermittent vomiting, hypotonia, lethargy, opisthotonos, terminal bleeding, seizures, and death in early infancy (Online Mendelian Inheritance in Man (OMIM) *200950).

[0053] PAP, a prostate epithelium-specific differentiation antigen produced by the prostate gland, has been used to diagnose and stage prostate cancer. In prostate carcinomas, the enzymatic activity of PAP was shown to be decreased compared with normal or benign prostate hypertrophy cells (Foti, A. G. et al. (1977) Cancer Res. 37: 4120-4124). Two forms of PAP have been identified, secreted and intracellular. Mature secreted PAP is detected in the seminal fluid and is active as a glycosylated homodimer with a molecular weight of approximately 100-kilodalton. Intracellular PAP is found to exhibit endogenous phosphotyrosyl protein phosphatase activity and is involved in regulating prostate cell growth (Meng, T. C. and Lin, M. F. (1998) 3. Biol. Chem. 34: 22096-22104).

[0054] Synaptojanin, a polyphosphoinositide phosphatase, dephosphorylates phosphoinositides at positions 3, 4 and 5 of the inositol ring. Synaptojanin is a major presynaptic protein found at clathrin-coated endocytic intermediates in nerve terminals, and binds the clathrin coat-associated protein, EPS15. This binding is mediated by the C-terminal region of synaptojanin-170, which has 3 Asp-Pro-Phe amino acid repeats. Further, this 3 residue repeat bad been found to be the binding site for the EH domains of EPS15 (Haffner, C. et al. (1997) FEBS Lett. 419:175-180). Additionally, synaptojanin may potentially regulate interactions of endocytic proteins with the plasma membrane, and be involved in synaptic vesicle recycling (Brodin, L. et al. (2000) Curr. Opin. Neurobiol. 10:312-320). Studies in mice with a targeted disruption in the synaptojanin 1 gene (Synj1) were shown to support coat formation of endocytic vesicles more effectively than was seen in wild-type mice, suggesting that Synj1 can act as a negative regulator of membrane-coat protein interactions. These findings provide genetic evidence for a crucial role of phosphoinositide metabolism in synaptic vesicle recycling (Cremona, O. et al. (1999) Cell 99:179-188).

[0055] The discovery of new kinases and phosphatases, and the polynucleotides encoding them, satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of cardiovascular diseases, immune system disorders, neurological disorders, disorders affecting growth and development, lipid disorders, cell proliferative disorders, and cancers, and in the assessment of the effects of exogenous compounds on the expression of nucleic acid and amino acid sequences of kinases and phosphatases.

SUMMARY OF THE INVENTION

[0056] The invention features purified polypeptides, kinases and phosphatases, referred to collectively as “KAP” and individually as “KAP-1,” “KAP-2,” “KAP-3,” “KAP-4,” “KAP-5,” “KAP-6,” “KAP-7,” “KAP-8,” “KAP-9,” “KAP-10,” “KAP-11,” “KAP-12,” “KAP-13,” “KAP-14,” “KAP-15,” “KAP-16,” “KAP-17,” “KAP-18,” “KAP-19,” and “KAP-20.” In one aspect, the invention provides an isolated polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1-20, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20. In one alternative, the invention provides an isolated polypeptide comprising the amino acid sequence of SEQ ID NO:1-20.

[0057] The invention further provides an isolated polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20. In one alternative, the polynucleotide encodes a polypeptide selected from the group consisting of SEQ ID NO:1-20. In another alternative, the polynucleotide is selected from the group consisting of SEQ ID NO:21-40.

[0058] Additionally, the invention provides a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20. In one alternative, the invention provides a cell transformed with the recombinant polynucleotide. In another alternative, the invention provides a transgenic organism comprising the recombinant polynucleotide.

[0059] The invention also provides a method for producing a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20. The method comprises a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding the polypeptide, and b) recovering the polypeptide so expressed.

[0060] Additionally, the invention provides an isolated antibody which specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20.

[0061] The invention further provides an isolated polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). In one alternative, the polynucleotide comprises at least 60 contiguous nucleotides.

[0062] Additionally, the invention provides a method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). The method comprises a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex, and optionally, if present, the amount thereof. In one alternative, the probe comprises at least 60 contiguous nucleotides.

[0063] The invention further provides a method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). The method comprises a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof, and, optionally, if present, the amount thereof.

[0064] The invention further provides a composition comprising an effective amount of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, and a pharmaceutically acceptable excipient. In one embodiment, the composition comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-20. The invention additionally provides a method of treating a disease or condition associated with decreased expression of functional KAP, comprising administering to a patient in need of such treatment the composition.

[0065] The invention also provides a method for screening a compound for effectiveness as an agonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting agonist activity in the sample. In one alternative, the invention provides a composition comprising an agonist compound identified by the method and a pharmaceutically acceptable excipient. In another alternative, the invention provides a method of treating a disease or condition associated with decreased expression of functional KAP, comprising administering to a patient in need of such treatment the composition.

[0066] Additionally, the invention provides a method for screening a compound for effectiveness as an antagonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting antagonist activity in the sample. In one alternative, the invention provides a composition comprising an antagonist compound identified by the method and a pharmaceutically acceptable excipient. In another alternative, the invention provides a method of treating a disease or condition associated with overexpression of functional KAP, comprising administering to a patient in need of such treatment the composition. The invention further provides a method of screening for a compound that specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20. The method comprises a) combining the polypeptide with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide to the test compound, thereby identifying a compound that specifically binds to the polypeptide.

[0067] The invention further provides a method of screening for a compound that modulates the activity of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20. The method comprises a) combining the polypeptide with at least one test compound under conditions permissive for the activity of the polypeptide, b) assessing the activity of the polypeptide in the presence of the test compound, and c) comparing the activity of the polypeptide in the presence of the test compound with the activity of the polypeptide in the absence of the test compound, wherein a change in the activity of the polypeptide in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide.

[0068] The invention further provides a method for screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40, the method comprising a) exposing a sample comprising the target polynucleotide to a compound, b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound.

[0069] The invention further provides a method for assessing toxicity of a test compound, said method comprising a) treating a biological sample containing nucleic acids with the test compound; b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40, iii) a polynucleotide having a sequence complementary to i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)iv). Hybridization occurs under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40, iii) a polynucleotide complementary to the polynucleotide of i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv). Alternatively, the target polynucleotide comprises a fragment of a polynucleotide sequence selected from the group consisting of i)-v) above; c) quantifying the amount of hybridization complex; and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound.

BRIEF DESCRIPTION OF THE TABLES

[0070] Table 1 summarizes the nomenclature for the full length polynucleotide and polypeptide sequences of the present invention.

[0071] Table 2 shows the GenBank identification number and annotation of the nearest GenBank homolog for polypeptides of the invention. The probability scores for the matches between each polypeptide and its homolog(s) are also shown.

[0072] Table 3 shows structural features of polypeptide sequences of the invention, including predicted motifs and domains, along with the methods, algorithms, and searchable databases used for analysis of the polypeptides.

[0073] Table 4 lists the cDNA and/or genomic DNA fragments which were used to assemble polynucleotide sequences of the invention, along with selected fragments of the polynucleotide sequences.

[0074] Table 5 shows the representative cDNA library for polynucleotides of the invention.

[0075] Table 6 provides an appendix which describes the tissues and vectors used for construction of the cDNA libraries shown in Table 5.

[0076] Table 7 shows the tools, programs, and algorithms used to analyze the polynucleotides and polypeptides of the invention, along with applicable descriptions, references, and threshold parameters.

DESCRIPTION OF THE INVENTION

[0077] Before the present proteins, nucleotide sequences, and methods are described, it is understood that this invention is not limited to the particular machines, materials and methods described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

[0078] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a host cell” includes a plurality of such host cells, and a reference to “an antibody” is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.

[0079] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any machines, materials, and methods similar or equivalent to those described herein can be used to practice or test the present invention, the preferred machines, materials and methods are now described. All publications mentioned herein are cited for the purpose of describing and disclosing the cell lines, protocols, reagents and vectors which are reported in the publications and which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

Definitions

[0080] “KAP” refers to the amino acid sequences of substantially purified KAP obtained from any species, particularly a mammalian species, including bovine, ovine, porcine, murine, equine, and human, and from any source, whether natural, synthetic, semi-synthetic, or recombinant.

[0081] The term “agonist” refers to a molecule which intensifies or mimics the biological activity of KAP. Agonists may include proteins, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of KAP either by directly interacting with KAP or by acting on components of the biological pathway in which KAP participates.

[0082] An “allelic variant” is an alternative form of the gene encoding KAP. Allelic variants may result from at least one mutation in the nucleic acid sequence and may result in altered mRNAs or in polypeptides whose structure or function may or may not be altered. A gene may have none, one, or many allelic variants of its naturally occurring form. Common mutational changes which give rise to allelic variants are generally ascribed to natural deletions, additions, or substitutions of nucleotides. Each of these types of changes may occur alone, or in combination with the others, one or more times in a given sequence.

[0083] “Altered” nucleic acid sequences encoding KAP include those sequences with deletions, insertions, or substitutions of different nucleotides, resulting in a polypeptide the same as KAP or a polypeptide with at least one functional characteristic of KAP. Included within this definition are polymorphisms which may or may not be readily detectable using a particular oligonucleotide probe of the polynucleotide encoding KAP, and improper or unexpected hybridization to allelic variants, with a locus other than the normal chromosomal locus for the polynucleotide sequence encoding KAP. The encoded protein may also be “altered,” and may contain deletions, insertions, or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent KAP. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues, as long as the biological or immunological activity of KAP is retained. For example, negatively charged amino acids may include aspartic acid and glutamic acid, and positively charged amino acids may include lysine and arginine. Amino acids with uncharged polar side chains having similar hydrophilicity values may include: asparagine and glutamine; and serine and threonine. Amino acids with uncharged side chains having similar hydrophilicity values may include: leucine, isoleucine, and valine; glycine and alanine; and phenylalanine and tyrosine.

[0084] The terms “amino acid” and “amino acid sequence” refer to an oligopeptide, peptide, polypeptide, or protein sequence, or a fragment of any of these, and to naturally occurring or synthetic molecules. Where “amino acid sequence” is recited to refer to a sequence of a naturally occurring protein molecule, “amino acid sequence” and like terms are not meant to limit the amino acid sequence to the complete native amino acid sequence associated with the recited protein molecule.

[0085] “Amplification” relates to the production of additional copies of a nucleic acid sequence. Amplification is generally carried out using polymerase chain reaction (PCR) technologies well known in the art.

[0086] The term “antagonist” refers to a molecule which inhibits or attenuates the biological activity of KAP. Antagonists may include proteins such as antibodies, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of KAP either by directly interacting with KAP or by acting on components of the biological pathway in which KAP participates.

[0087] The term “antibody” refers to intact immunoglobulin molecules as well as to fragments thereof, such as Fab, F(ab′)₂, and Fv fragments, which are capable of binding an epitopic determinant. Antibodies that bind KAP polypeptides can be prepared using intact polypeptides or using fragments containing small peptides of interest as the immunizing antigen. The polypeptide or oligopeptide used to immunize an animal (e.g., a mouse, a rat, or a rabbit) can be derived from the translation of RNA, or synthesized chemically, and can be conjugated to a carrier protein if desired. Commonly used carriers that are chemically coupled to peptides include bovine serum albumin, thyroglobulin, and keyhole limpet hemocyanin (KLH). The coupled peptide is then used to immunize the animal.

[0088] The term “antigenic determinant” refers to that region of a molecule (i.e., an epitope) that makes contact with a particular antibody. When a protein or a fragment of a protein is used to immunize a host animal, numerous regions of the protein may induce the production of antibodies which bind specifically to antigenic determinants (particular regions or three-dimensional structures on the protein). An antigenic determinant may compete with the intact antigen (i.e., the immunogen used to elicit the immune response) for binding to an antibody.

[0089] The term “aptamer” refers to a nucleic acid or oligonucleotide molecule that binds to a specific molecular target. Aptamers are derived from an in vitro evolutionary process (e.g., SELEX (Systematic Evolution of Ligands by EXponential Enrichment), described in U.S. Pat. No. 5,270,163), which selects for target-specific aptamer sequences from large combinatorial libraries. Aptamer compositions may be double-stranded or single-stranded, and may include deoxyribonucleotides, ribonucleotides, nucleotide derivatives, or other nucleotide-like molecules. The nucleotide components of an aptamer may have modified sugar groups (e.g., the 2′-OH group of a ribonucleotide may be replaced by 2′-F or 2′-NH₂), which may improve a desired property, e.g., resistance to nucleases or longer lifetime in blood. Aptamers may be conjugated to other molecules, e.g., a high molecular weight carrier to slow clearance of the aptamer from the circulatory system. Aptamers may be specifically cross-linked to their cognate ligands, e.g., by photo-activation of a cross-linker. (See, e.g., Brody, E. N. and L. Gold (2000) J. Biotechnol. 74:5-13.)

[0090] The term “intramer” refers to an aptamer which is expressed in vivo. For example, a vaccinia virus-based RNA expression system has been used to express specific RNA aptamers at high levels in the cytoplasm of leukocytes (Blind, M. et al. (1999) Proc. Natl Acad. Sci. USA 96:3606-3610).

[0091] The term “spiegelmer” refers to an aptamer which includes L-DNA, L-RNA, or other left-handed nucleotide derivatives or nucleotide-like molecules. Aptamers containing left-handed nucleotides are resistant to degradation by naturally occurring enzymes, which normally act on substrates containing right-handed nucleotides.

[0092] The term “antisense” refers to any composition capable of base-pairing with the “sense” (coding) strand of a specific nucleic acid sequence. Antisense compositions may include DNA; RNA; peptide nucleic acid (PNA); oligonucleotides having modified backbone linkages such as phosphorothioates, methylphosphonates, or benzylphosphonates; oligonucleotides having modified sugar groups such as 2′-methoxyethyl sugars or 2′-methoxyethoxy sugars; or oligonucleotides having modified bases such as 5-methyl cytosine, 2′-deoxyuracil, or 7-deaza-2′-deoxyguanosine. Antisense molecules may be produced by any method including chemical synthesis or transcription. Once introduced into a cell, the complementary antisense molecule base-pairs with a naturally occurring nucleic acid sequence produced by the cell to form duplexes which block either transcription or translation. The designation “negative” or “minus” can refer to the antisense strand, and the designation “positive” or “plus” can refer to the sense strand of a reference DNA molecule.

[0093] The term “biologically active” refers to a protein having structural, regulatory, or biochemical functions of a naturally occurring molecule. Likewise, “immunologically active” or “immunogenic” refers to the capability of the natural, recombinant, or synthetic KAP, or of any oligopeptide thereof, to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.

[0094] “Complementary” describes the relationship between two single-stranded nucleic acid sequences that anneal by base-pairing. For example, 5′-AGT-3′ pairs with its complement, 3′-TCA-5′.

[0095] A “composition comprising a given polynucleotide sequence” and a “composition comprising a given amino acid sequence” refer broadly to any composition containing the given polynucleotide or amino acid sequence. The composition may comprise a dry formulation or an aqueous solution. Compositions comprising polynucleotide sequences encoding KAP or fragments of KAP may be employed as hybridization probes. The probes may be stored in freeze-dried form and may be associated with a stabilizing agent such as a carbohydrate. In hybridizations, the probe may be deployed in an aqueous solution containing salts (e.g., NaCl), detergents (e.g., sodium dodecyl sulfate; SDS), and other components (e.g., Denhardt's solution, dry milk, salmon sperm DNA, etc.).

[0096] “Consensus sequence” refers to a nucleic acid sequence which has been subjected to repeated DNA sequence analysis to resolve uncalled bases, extended using the XL-PCR kit (Applied Biosystems, Foster City Calif.) in the 5′ and/or the 3′ direction, and resequenced, or which has been assembled from one or more overlapping cDNA, EST, or genomic DNA fragments using a computer program for fragment assembly, such as the GELVIEW fragment assembly system (GCG, Madison Wis.) or Phrap (University of Washington, Seattle Wash.). Some sequences have been both extended and assembled to produce the consensus sequence.

[0097] “Conservative amino acid substitutions” are those substitutions that are predicted to least interfere with the properties of the original protein, i.e., the structure and especially the function of the protein is conserved and not significantly changed by such substitutions. The table below shows *amino acids which may be substituted for an original amino acid in a protein and which are regarded as conservative amino acid substitutions. Original Residue Conservative Substitution Ala Gly, Ser Arg His, Lys Asn Asp, Gln, His Asp Asn, Glu Cys Ala, Ser Gln Asn, Glu, His Glu Asp, Gln, His Gly Ala His Asn, Arg, Gln, Glu Ile Leu, Val Leu Ile, Val Lys Arg, Gln, Glu Met Leu, Ile Phe His, Met, Leu, Trp, Tyr Ser Cys, Thr Thr Ser, Val Trp Phe, Tyr Tyr His, Phe, Trp Val Ile, Leu, Thr

[0098] Conservative amino acid substitutions generally maintain (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a beta sheet or alpha helical conformation, (b) the charge or hydrophobicity of the molecule at the site of the substitution, and/or (c) the bulk of the side chain.

[0099] A “deletion” refers to a change in the amino acid or nucleotide sequence that results in the absence of one or more amino acid residues or nucleotides.

[0100] The term “derivative” refers to a chemically modified polynucleotide or polypeptide. Chemical modifications of a polynucleotide can include, for example, replacement of hydrogen by an alkyl, acyl, hydroxyl, or amino group. A derivative polynucleotide encodes a polypeptide which retains at least one biological or immunological function-of the natural molecule. A derivative polypeptide is one modified by glycosylation, pegylation, or any similar process that retains at least one biological or immunological function of the polypeptide from which it was derived.

[0101] A “detectable label” refers to a reporter molecule or enzyme that is capable of generating a measurable signal and is covalently or noncovalently joined to a polynucleotide or polypeptide.

[0102] “Differential expression” refers to increased or upregulated; or decreased, downregulated, or absent gene or protein expression, determined by comparing at least two different samples. Such comparisons may be carried out between, for example, a treated and an untreated sample, or a diseased and a normal sample.

[0103] “Exon shuffling” refers to the recombination of different coding regions (exons). Since an exon may represent a structural or functional domain of the encoded protein, new proteins may be assembled through the novel reassortment of stable substructures, thus allowing acceleration of the evolution of new protein functions.

[0104] A “fragment” is a unique portion of KAP or the polynucleotide encoding KAP which is identical in sequence to but shorter in length than the parent sequence. A fragment may comprise up to the entire length of the defined sequence, minus one nucleotide/amino acid residue. For example, a fragment may comprise from 5 to 1000 contiguous nucleotides or amino acid residues. A fragment used as a probe, primer, antigen, therapeutic molecule, or for other purposes, may be at least 5, 10, 15, 16, 20, 25, 30, 40, 50, 60, 75, 100, 150, 250 or at least 500 contiguous nucleotides or amino acid residues in length. Fragments may be preferentially selected from certain regions of a molecule. For example, a polypeptide fragment may comprise a certain length of contiguous amino acids selected from the first 250 or 500 amino acids (or first 25% or 50%) of a polypeptide as shown in a certain defined sequence. Clearly these lengths are exemplary, and any length that is supported by the specification, including the Sequence Listing, tables, and figures, may be encompassed by the present embodiments.

[0105] A fragment of SEQ D NO:21-40 comprises a region of unique polynucleotide sequence that specifically identifies SEQ ID NO:21-40, for example, as distinct from any other sequence in the genome from which the fragment was obtained. A fragment of SEQ ID NO:21-40 is useful, for example, in hybridization and amplification technologies and in analogous methods that distinguish SEQ ID NO:21-40 from related polynucleotide sequences. The precise length of a fragment of SEQ ID NO:21-40 and the region of SEQ ID NO:21-40 to which the fragment corresponds are routinely determinable by one of ordinary skill in the art based on the intended purpose for the fragment.

[0106] A fragment of SEQ ID NO:1-20 is encoded by a fragment of SEQ ID NO:21-40. A fragment of SEQ ID NO:1-20 comprises a region of unique amino acid sequence that specifically identifies SEQ ID NO:1-20. For example, a fragment of SEQ ID NO:1-20 is useful as an immunogenic peptide for the development of antibodies that specifically recognize SEQ ID NO:1-20. The precise length of a fragment of SEQ ID NO:1-20 and the region of SEQ ID NO:1-20 to which the fragment corresponds are routinely determinable by one of ordinary skill in the art based on the intended purpose for the fragment.

[0107] A “full length” polynucleotide sequence is one containing at least a translation initiation codon (e.g., methionine) followed by an open reading frame and a translation termination codon. A “full length” polynucleotide sequence encodes a “full length” polypeptide sequence.

[0108] “Homology” refers to sequence similarity or, interchangeably, sequence identity, between two or more polynucleotide sequences or two or more polypeptide sequences.

[0109] The terms “percent identity” and “% identity,” as applied to polynucleotide sequences, refer to the percentage of residue matches between at least two polynucleotide sequences aligned using a standardized algorithm. Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences.

[0110] Percent identity between polynucleotide sequences may be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN version 3.12e sequence alignment program. This program is part of the LASERGENE software package, a suite of molecular biological analysis programs (DNASTAR, Madison Wis.). CLUSTAL V is described in Higgins, D. G. and P. M. Sharp (1989) CABIOS 5:151-153 and in Higgins, D. G. et al. (1992) CABIOS 8:189-191. For pairwise alignments of polynucleotide sequences, the default parameters are set as follows: Ktuple=2, gap penalty=5, window=4, and “diagonals saved”=4. The “weighted” residue weight table is selected as the default. Percent identity is reported by CLUSTAL V as the “percent similarity” between aligned polynucleotide sequences.

[0111] Alternatively, a suite of commonly used and freely available sequence comparison algorithms is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S. F. et al. (1990) J. Mol. Biol. 215:403-410), which is available from several sources, including the NCBL, Bethesda, Md., and on the Internet at http://www.ncbi.nlm.nih.gov/BLAST/. The BLAST software suite includes various sequence analysis programs including “blastn,” that is used to align a known polynucleotide sequence with other polynucleotide sequences from a variety of databases. Also available is a tool called “BLAST 2 Sequences” that is used for direct pairwise comparison of two nucleotide sequences. “BLAST 2 Sequences” can be accessed and used interactively at http://www.ncbi.nlm.nih.gov/gorf/b12.html. The “BLAST 2 Sequences” tool can be used for both blastn and blastp (discussed below). BLAST programs are commonly used with gap and other parameters set to default settings. For example, to compare two nucleotide sequences, one may use blastn with the “BLAST 2 Sequences” tool Version 2.0.12 (Apr. 21, 2000) set at default parameters. Such default parameters may be, for example:

[0112] Matrix: BLOSUM62

[0113] Reward for match: 1

[0114] Penalty for mismatch: −2

[0115] Open Gap: 5 and Extension Gap: 2 penalties

[0116] Gap x drop-off: 50

[0117] Expect: 10

[0118] Word Size: 11

[0119] Filter: on

[0120] Percent identity may be measured over the length of an entire defined sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined sequence, for instance, a fragment of at least 20, at least 30, at least 40, at least 50, at least 70, at least 100, or at least 200 contiguous nucleotides. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures, or Sequence Listing, may be used to describe a length over which percentage identity may be measured.

[0121] Nucleic acid sequences that do not show a high degree of identity may nevertheless encode similar amino acid sequences due to the degeneracy of the genetic code. It is understood that changes in a nucleic acid sequence can be made using this degeneracy to produce multiple nucleic acid sequences that all encode substantially the same protein.

[0122] The phrases “percent identity” and “% identity,” as applied to polypeptide sequences, refer to the percentage of residue matches between at least two polypeptide sequences aligned using a standardized algorithm. Methods of polypeptide sequence alignment are well-known. Some alignment methods take into account conservative amino acid substitutions. Such conservative substitutions, explained in more detail above, generally preserve the charge and hydrophobicity at the site of substitution, thus preserving the structure (and therefore function) of the polypeptide.

[0123] Percent identity between polypeptide sequences may be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN version 3.12e sequence alignment program (described and referenced above). For pairwise alignments of polypeptide sequences using CLUSTAL V, the default parameters are set as follows: Ktuple=1, gap penalty=3, window=5, and “diagonals saved”=5. The PAM250 matrix is selected as the default residue weight table. As with polynucleotide alignments, the percent identity is reported by CLUSTAL V as the “percent similarity” between aligned polypeptide sequence pairs.

[0124] Alternatively the NCBI BLAST software suite may be used. For example, for a pairwise comparison of two polypeptide sequences, one may use the “BLAST 2 Sequences” tool Version 2.0.12 (Apr. 21, 2000) with blastp set at default parameters. Such default parameters may be, for example:

[0125] Matrix: BLOSUM62

[0126] Open Gap: 11 and Extension Gap: 1 penalties

[0127] Gap x drop-off: 50

[0128] Expect: 10

[0129] Word Size: 3

[0130] Filter: on

[0131] Percent identity may be measured over the length of an entire defined polypeptide sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures or Sequence Listing, may be used to describe a length over which percentage identity may be measured.

[0132] “Human artificial chromosomes” (HACs) are linear microchromosomes which may contain DNA sequences of about 6 kb to 10 Mb in size and which contain all of the elements required for chromosome replication, segregation and maintenance.

[0133] The term “humanized antibody” refers to an antibody molecule in which the amino acid sequence in the non-antigen binding regions has been altered so that the antibody more closely resembles a human antibody, and still retains its original binding ability.

[0134] “Hybridization” refers to the process by which a polynucleotide strand anneals with a complementary strand through base pairing under defined hybridization conditions. Specific hybridization is an indication that two nucleic acid sequences share a high degree of complementarity. Specific hybridization complexes form under permissive annealing conditions and remain hybridized after the “washing” step(s). The washing step(s) is particularly important in determining the stringency of the hybridization process, with more stringent conditions allowing less non-specific binding, i.e., binding between pairs of nucleic acid strands that are not perfectly matched. Permissive conditions for annealing of nucleic acid sequences are routinely determinable by one of ordinary skill in the art and may be consistent among hybridization experiments, whereas wash conditions may be varied among experiments to achieve the desired stringency, and therefore hybridization specificity. Permissive annealing conditions occur, for example, at 68° C. in the presence of about 6×SSC, about 1% (w/v) SDS, and about 100 μg/ml sheared, denatured salmon sperm DNA.

[0135] Generally, stringency of hybridization is expressed, in part, with reference to the temperature under which the wash step is carried out. Such wash temperatures are typically selected to be about 5° C. to 20° C. lower than the thermal melting point (T_(m)) for the specific sequence at a defined ionic strength and pH. The T_(m) is the temperature (under defined ionic strength and pH) at which 50% of the target sequence hybridizes to a perfectly matched probe. An equation for calculating T_(m) and conditions for nucleic acid hybridization are well known and can be found in Sambrook, J. et al. (1989) Molecular Cloning: A Laboratory Manual, 2^(nd) ed., vol. 1-3, Cold Spring Harbor Press, Plainview N.Y.; specifically see volume 2, chapter 9.

[0136] High stringency conditions for hybridization between polynucleotides of the present invention include wash conditions of 68° C. in the presence of about 0.2×SSC and about 0.1% SDS, for 1 hour. Alternatively, temperatures of about 65° C., 60° C., 55° C., or 42° C. may be used. SSC concentration may be varied from about 0.1 to 2×SSC, with SDS being present at about 0.1%. Typically, blocking reagents are used to block non-specific hybridization. Such blocking reagents include, for instance, sheared and denatured salmon sperm DNA at about 100-200 μg/ml. Organic solvent, such as formamide at a concentration of about 35-50% v/v, may also be used under particular circumstances, such as for RNA:DNA hybridizations. Useful variations on these wash conditions will be readily apparent to those of ordinary skill in the art. Hybridization, particularly under high stringency conditions, may be suggestive of evolutionary similarity between the nucleotides. Such similarity is strongly indicative of a similar role for the nucleotides and their encoded polypeptides.

[0137] The term “hybridization complex” refers to a complex formed between two nucleic acid sequences by virtue of the formation of hydrogen bonds between complementary bases. A hybridization complex may be formed in solution (e.g., C₀t or R₀t analysis) or formed between one nucleic acid sequence present in solution and another nucleic acid sequence immobilized on a solid support (e.g., paper, membranes, filters, chips, pins or glass slides, or any other appropriate substrate to which cells or their nucleic acids have been fixed).

[0138] The words “insertion” and “addition” refer to changes in an amino acid or nucleotide sequence resulting in the addition of one or more amino acid residues or nucleotides, respectively.

[0139] “Immune response” can refer to conditions associated with inflammation, trauma, immune disorders, or infectious or genetic disease, etc. These conditions can be characterized by expression of various factors, e.g., cytokines, chemokines, and other signaling molecules, which may affect cellular and systemic defense systems.

[0140] An “immunogenic fragment” is a polypeptide or oligopeptide fragment of KAP which is capable of eliciting an immune response when introduced into a living organism, for example, a mammal. The term “immunogenic fragment” also includes any polypeptide or oligopeptide fragment of KAP which is useful in any of the antibody production methods disclosed herein or known in the art.

[0141] The term “microarray” refers to an arrangement of a plurality of polynucleotides, polypeptides, or other chemical compounds on a substrate.

[0142] The terms “element” and “array element” refer to a polynucleotide, polypeptide, or other chemical compound having a unique and defined position on a microarray.

[0143] The term “modulate” refers to a change in the activity of KAP. For example, modulation may cause an increase or a decrease in protein activity, binding characteristics, or any other biological, functional, or immunological properties of KAP.

[0144] The phrases “nucleic acid” and “nucleic acid sequence” refer to a nucleotide, oligonucleotide, polynucleotide, or any fragment thereof. These phrases also refer to DNA or RNA of genomic or synthetic origin which may be single-stranded or double-stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA), or to any DNA-like or RNA-like material.

[0145] “Operably linked” refers to the situation in which a first nucleic acid sequence is placed in a functional relationship with a second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Operably linked DNA sequences may be in close proximity or contiguous and, where necessary to join two protein coding regions, in the same reading frame.

[0146] “Peptide nucleic acid” (PNA) refers to an antisense molecule or anti-gene agent which comprises an oligonucleotide of at least about 5 nucleotides in length linked to a peptide backbone of amino acid residues ending in lysine. The terminal lysine confers solubility to the composition. PNAs preferentially bind complementary single stranded DNA or RNA and stop transcript elongation, and may be pegylated to extend their lifespan in the cell.

[0147] “Post-translational modification” of an KAP may involve lipidation, glycosylation, phosphorylation, acetylation, racemization, proteolytic cleavage, and other modifications known in the art. These processes may occur synthetically or biochemically. Biochemical modifications will vary by cell type depending on the enzymatic milieu of KAP.

[0148] “Probe” refers to nucleic acid sequences encoding KAP, their complements, or fragments thereof, which are used to detect identical, allelic or related nucleic acid sequences. Probes are isolated oligonucleotides or polynucleotides attached to a detectable label or reporter molecule. Typical labels include radioactive isotopes, ligands, chemiluminescent agents, and enzymes. “Primers” are short nucleic acids, usually DNA oligonucleotides, which may be annealed to a target polynucleotide by complementary base-pairing. The primer may then be extended along the target DNA strand by a DNA polymerase enzyme. Primer pairs can be used for amplification (and identification) of a nucleic acid sequence, e.g., by the polymerase chain reaction (PCR).

[0149] Probes and primers as used in the present invention typically comprise at least 15 contiguous nucleotides of a known sequence. In order to enhance specificity, longer probes and primers may also be employed, such as probes and primers that comprise at least 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, or at least 150 consecutive nucleotides of the disclosed nucleic acid sequences. Probes and primers may be considerably longer than these examples, and it is understood that any length supported by the specification, including the tables, figures, and Sequence Listing, may be used.

[0150] Methods for preparing and using probes and primers are described in the references, for example Sambrook, J. et al. (1989) Molecular Cloning: A Laboratory Manual, 2^(nd) ed., vol. 1-3, Cold Spring Harbor Press, Plainview N.Y.; Ausubel, F. M. et al. (1987) Current Protocols in Molecular Biology, Greene Publ. Assoc. & Wiley-Intersciences, New York N.Y.; Innis, M. et al. (1990) PCR Protocols. A Guide to Methods and Applications, Academic Press, San Diego Calif. PCR primer pairs can be derived from a known sequence, for example, by using computer programs intended for that purpose such as Primer (Version 0.5, 1991, Whitehead Institute for Biomedical Research, Cambridge Mass.).

[0151] Oligonucleotides for use as primers are selected using software known in the art for such purpose. For example, OLIGO 4.06 software is useful for the selection of PCR primer pairs of up to 100 nucleotides each, and for the analysis of oligonucleotides and larger polynucleotides of up to 5,000 nucleotides from an input polynucleotide sequence of up to 32 kilobases. Similar primer selection programs have incorporated additional features for expanded capabilities. For example, the PrimOU primer selection program (available to the public from the Genome Center at University of Texas South West Medical Center, Dallas Tex.) is capable of choosing specific primers from megabase sequences and is thus useful for designing primers on a genome-wide scope. The Primer3 primer selection program (available to the public from the Whitehead Institute/MIT Center for Genome Research, Cambridge Mass.) allows the user to input a “mispriming library,” in which sequences to avoid as primer binding sites are user-specified. Primer3 is useful, in particular, for the selection of oligonucleotides for microarrays. (The source code for the latter two primer selection programs may also be obtained from their respective sources and modified to meet the user's specific needs.) The PrimeGen program (available to the public from the UK Human Genome Mapping Project Resource Centre, Cambridge UK) designs primers based on multiple sequence alignments, thereby allowing selection of primers that hybridize to either the most conserved or least conserved regions of aligned nucleic acid sequences. Hence, this program is useful for identification of both unique and conserved oligonucleotides and polynucleotide fragments. The oligonucleotides and polynucleotide fragments identified by any of the above selection methods are useful in hybridization technologies, for example, as PCR or sequencing primers, microarray elements, or specific probes to identify fully or partially complementary polynucleotides in a sample of nucleic acids. Methods of oligonucleotide selection are not limited to those described above.

[0152] A “recombinant nucleic acid” is a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two or more otherwise separated segments of sequence. This artificial combination is often accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, e.g., by genetic engineering techniques such as those described in Sambrook, supra. The term recombinant includes nucleic acids that have been altered solely by addition, substitution, or deletion of a portion of the nucleic acid. Frequently, a recombinant nucleic acid may include a nucleic acid sequence operably linked to a promoter sequence. Such a recombinant nucleic acid may be part of a vector that is used, for example, to transform a cell.

[0153] Alternatively, such recombinant nucleic acids may be part of a viral vector, e.g., based on a vaccinia virus, that could be use to vaccinate a mammal wherein the recombinant nucleic acid is expressed, inducing a protective immunological response in the mammal.

[0154] A “regulatory element” refers to a nucleic acid sequence usually derived from untranslated regions of a gene and includes enhancers, promoters, introns, and 5′ and 3′ untranslated regions (UTRs). Regulatory elements interact with host or viral proteins which control transcription, translation, or RNA stability.

[0155] “Reporter molecules” are chemical or biochemical moieties used for labeling a nucleic acid, amino acid, or antibody. Reporter molecules include radionuclides; enzymes; fluorescent, chemiluminescent, or chromogenic agents; substrates; cofactors; inhibitors; magnetic particles; and other moieties known in the art.

[0156] An “RNA equivalent,” in reference to a DNA sequence, is composed of the same linear sequence of nucleotides as the reference DNA sequence with the exception that all occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.

[0157] The term “sample” is used in its broadest sense. A sample suspected of containing KAP, nucleic acids encoding KAP, or fragments thereof may comprise a bodily fluid; an extract from a cell, chromosome, organelle, or membrane isolated from a cell; a cell; genomic DNA, RNA, or cDNA, in solution or bound to a substrate; a tissue; a tissue print; etc.

[0158] The terms “specific binding” and “specifically binding” refer to that interaction between a protein or peptide and an agonist, an antibody, an antagonist, a small molecule, or any natural or synthetic binding composition. The interaction is dependent upon the presence of a particular structure of the protein, e.g., the antigenic determinant or epitope, recognized by the binding molecule. For example, if an antibody is specific for epitope “A,” the presence of a polypeptide comprising the epitope A, or the presence of free unlabeled A, in a reaction containing free labeled A and the antibody will reduce the amount of labeled A that binds to the antibody.

[0159] The term “substantially purified” refers to nucleic acid or amino acid sequences that are removed from their natural environment and are isolated or separated, and are at least 60% free, preferably at least 75% free, and most preferably at least 90% free from other components with which they are naturally associated.

[0160] A “substitution” refers to the replacement of one or more amino acid residues or nucleotides by different amino acid residues or nucleotides, respectively.

[0161] “Substrate” refers to any suitable rigid or semi-rigid support including membranes, filters, chips, slides, wafers, fibers, magnetic or nonmagnetic beads, gels, tubing, plates, polymers, microparticles and capillaries. The substrate can have a variety of surface forms, such as wells, trenches, pins, channels and pores, to which polynucleotides or polypeptides are bound.

[0162] A “transcript image” or “expression profile” refers to the collective pattern of gene expression by a particular cell type or tissue under given conditions at a given time.

[0163] “Transformation” describes a process by which exogenous DNA is introduced into a recipient cell. Transformation may occur under natural or artificial conditions according to various methods well known in the art, and may rely on any known method for the insertion of foreign nucleic acid sequences into a prokaryotic or eukaryotic host cell. The method for transformation is selected based on the type of host cell being transformed and may include, but is not limited to, bacteriophage or viral infection, electroporation, heat shock, lipofection, and particle bombardment The term “transformed cells” includes stably transformed cells in which the inserted DNA is capable of replication either as an autonomously replicating plasmid or as part of the host chromosome, as well as transiently transformed cells which express the inserted DNA or RNA for limited periods of time.

[0164] A “transgenic organism,” as used herein, is any organism, including but not limited to animals and plants, in which one or more of the cells of the organism contains heterologous nucleic acid introduced by way of human intervention, such as by transgenic techniques well known in the art. The nucleic acid is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, by way of deliberate genetic manipulation, such as by microinjection or by infection with a recombinant virus. The term genetic manipulation does not include classical cross-breeding, or in vitro fertilization, but rather is directed to the introduction of a recombinant DNA molecule. The transgenic organisms contemplated in accordance with the present invention include bacteria, cyanobacteria, fungi, plants and animals. The isolated DNA of the present invention can be introduced into the host by methods known in the art, for example infection, transfection, transformation or transconjugation. Techniques for transferring the DNA of the present invention into such organisms are widely known and provided in references such as Sambrook et al. (1989), supra.

[0165] A “variant” of a particular nucleic acid sequence is defined as a nucleic acid sequence having at least 40% sequence identity to the particular nucleic acid sequence over a certain length of one of the nucleic acid sequences using blastn with the “BLAST 2 Sequences” tool Version 2.0.9 (May 7, 1999) set at default parameters. Such a pair of nucleic acids may show, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length. A variant may be described as, for example, an “allelic” (as defined above), “splice,” “species,” or “polymorphic” variant A splice variant may have significant identity to a reference molecule, but will generally have a greater or lesser number of polynucleotides due to alternate splicing of exons during mRNA processing. The corresponding polypeptide may possess additional functional domains or lack domains that are present in the reference molecule. Species variants are polynucleotide sequences that vary from one species to another. The resulting polypeptides will generally have significant amino acid identity relative to each other. A polymoiphic variant is a variation in the polynucleotide sequence of a particular gene between individuals of a given species. Polymorphic variants also may encompass “single nucleotide polymorphisms” (SNPs) in which the polynucleotide sequence varies by one nucleotide base. The presence of SNPs may be indicative of, for example, a certain population, a disease state, or a propensity for a disease state.

[0166] A “variant” of a particular polypeptide sequence is defined as a polypeptide sequence having at least 40% sequence identity to the particular polypeptide sequence over a certain length of one of the polypeptide sequences using blastp with the “BLAST 2 Sequences” tool Version 2.0.9 (May 7, 1999) set at default parameters. Such a pair of polypeptides may show, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length of one of the polypeptides.

The Invention

[0167] The invention is based on the discovery of new human kinases and phosphatases (KAP), the polynucleotides encoding KAP, and the use of these compositions for the diagnosis, treatment, or prevention of cardiovascular diseases, immune system disorders, neurological disorders, disorders affecting growth and development, lipid disorders, cell proliferative disorders, and cancers.

[0168] Table 1 summarzes the nomenclature for the full length polynucleotide and polypeptide sequences of the invention. Each polynucleotide and its corresponding polypeptide are correlated to a single Incyte project identification number (Incyte Project ID). Each polypeptide sequence is denoted by both a polypeptide sequence identification number (Polypeptide SEQ ID NO:) and an Incyte polypeptide sequence number (Incyte Polypeptide ID) as shown. Each polynucleotide sequence is denoted by both a polynucleotide sequence identification number (Polynucleotide SEQ ID NO:) and an Incyte polynucleotide consensus sequence number (Incyte Polynucleotide ID) as shown.

[0169] Table 2 shows sequences with homology to the polypeptides of the invention as identified by BLAST analysis against the GenBank protein (genpept) database. Columns 1 and 2 show the polypeptide sequence identification number (Polypeptide SEQ ID NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide ID) for polypeptides of the invention. Column 3 shows the GenBank identification number (GenBank ID NO:) of the nearest GenBank homolog. Column 4 shows the probability scores for the matches between each polypeptide and its homolog(s). Column 5 shows the annotation of the GenBank homolog(s) along with relevant citations where applicable, all of which are expressly incorporated by reference herein.

[0170] Table 3 shows various structural features of the polypeptides of the invention. Columns 1 and 2 show the polypeptide sequence identification number (SEQ ID NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide ID) for each polypeptide of the invention. Column 3 shows the number of amino acid residues in each polypeptide. Column 4 shows potential phosphorylation sites, and column 5 shows potential glycosylation sites, as determined by the MOTIFS program of the GCG sequence analysis software package (Genetics Computer Group, Madison Wis.). Column 6 shows amino acid residues comprising signature sequences, domains, and motifs. Column 7 shows analytical methods for protein structure/function analysis and in some cases, searchable databases to which the analytical methods were applied.

[0171] Together, Tables 2 and 3 summarize the properties of polypeptides of the invention, and these properties establish that the claimed polypeptides are kinases and phosphatases. For example, SEQ ID NO:1 is 79% identical to rat protein tyrosine phosphatase TD14 (GenBank ID g3598974) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID NO:1 also contains protein-tyrosine phosphatase domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS, PROFILESCAN and MOTIFS analyses provide further corroborative evidence that SEQ ID NO:1 is a protein-tyrosine phosphatase.

[0172] In an alternative example, SEQ ID NO:3 is 34% identical to Fagus sylvatica protein phosphatase 2C (PP2C, GenBank ID g7768151) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 6.4e-17, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID NO:3 also shares 45% identity with a putative Caenorhabditis elegans PP2C (GenBank ID g2804429), based on BLAST analysis, with a probability score of 2.4e-71. SEQ ID NO:3 contains protein phosphatase 2C domains as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BUMPS analysis provide further corroborative evidence that SEQ ID NO:3 is a protein phosphatase 2C.

[0173] In an alternative example, SEQ ID NO:5 is 25% identical to human protein kinase PAK5 (GenBank ID g7649810) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 7.2e-14, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID NO:5 also contains a eukaryotic protein kinase domain as determined by searching for statistically significant matches in the hidden Markov model (MM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from TMAP analysis as well as BLIMPS and BLAST analyses of the PRODOM and DOMO databases provide further corroborative evidence that SEQ ID NO:5 is a membrane-bound kinase.

[0174] In an alternative example, SEQ ID NO:6 is 1511 amino acid residues in length and is 97% identical over 1494 residues to human MEK kinase I (GenBank ID g2815888) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID NO:6 also contains a eukaryotic protein kinase domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS, MOTIFS, and PROFILESCAN analyses provide further corroborative evidence that SEQ ID NO:6 is protein kinase. In an alternative example, SEQ ID NO:9 is 87% identical to murine protein kinase (GenBank ID g406058) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID NO:9 also contains an eukaryotic protein kinase domain and a PDZ domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS, MOTIFS, and PROFILESCAN analyses provide further corroborative evidence that SEQ ID NO:9 is a protein kinase.

[0175] In an alternative example, SEQ ID NO:16 is 61% identical to human mitogen-activated kinase kinase kinase 5 (GenBank ID g1679668) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID NO:16 also contains a eukaryotic protein kinase domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS, MOTIFS, and PROFILESCAN analyses provide further corroborative evidence that SEQ ID NO:16 is a mitogen activated protein kinase kinase kinase.

[0176] In an alternative example, SEQ ID NO:18 is 83% identical from residues 4 to 372 to mouse protein kinase (GenBank ID g406058) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID NO:18 also contains a eukaryotic protein kinase domain and a PDZ domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS, MOTIFS, and PROFILESCAN analyses provide further corroborative evidence that SEQ ID NO:18 is a serine/threonine protein kinase.

[0177] In an alternative example, SEQ ID NO:19 is 95% identical, from residue M1 to residue V988, to Rattus norvegius mytonic dystrophy kinase-related Cdc42-binding kinase (GenBank ID g2736151) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID NO:19 also contains a protein kinase C terminal domain and a eukaryotic protein kinase domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS, MOTIFS, and additional BLAST analyses provide further corroborative evidence that SEQ ID NO:19 is a protein kinase.

[0178] SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:10-15, SEQ ID NO:17, and SEQ ID NO:20 were analyzed and annotated in a similar manner. The algorithms and parameters for the analysis of SEQ ID NO:1-20 are described in Table 7.

[0179] As shown in Table 4, the full length polynucleotide sequences of the present invention were assembled using cDNA sequences or coding (exon) sequences derived from genomic DNA, or any combination of these two types of sequences. Column 1 lists the polynucleotide sequence identification number (Polynucleotide SEQ ID NO:), the corresponding Incyte polynucleotide consensus sequence number (Incyte ID) for each polynucleotide of the invention, and the length of each polynucleotide sequence in basepairs. Column 2 shows the nucleotide start (5′) and stop (3′) positions of the cDNA and/or genomic sequences used to assemble the full length polynucleotide sequences of the invention, and of fragments of the polynucleotide sequences which are useful, for example, in hybridization or amplification technologies that identify SEQ ID NO:21-40 or that distinguish between SEQ ID NO:21-40 and related polynucleotide sequences.

[0180] The polynucleotide fragments described in Column 2 of Table 4 may refer specifically, for example, to Incyte cDNAs derived from tissue-specific cDNA libraries or from pooled cDNA libraries. Alternatively, the polynucleotide fragments described in column 2 may refer to GenBank cDNAs or ESTs which contributed to the assembly of the full length polynucleotide sequences. In addition, the polynucleotide fragments described in column 2 may identify sequences derived from the ENSEMBL (The Sanger Centre, Cambridge, UK) database (i.e., those sequences including the designation “ENST”). Alternatively, the polynucleotide fragments described in column 2 may be derived from the NCBI RefSeq Nucleotide Sequence Records Database (i.e., those sequences including the designation “NM” or “NT′) or the NCBI RefSeq Protein Sequence Records (i.e., those sequences including the designation “NP”). Alternatively, the polynucleotide fragments described in column 2 may refer to assemblages of both cDNA and Genscan-predicted exons brought together by an “exon stitching” algorithm. For example, a polynucleotide sequence identified as FL_XXXXXX_N_(1—)N_(2—)YYYYY_N_(3—)N₄ represents a “stitched” sequence in which XXXXXX is the identification number of the cluster of sequences to which the algorithm was applied, and YYYYY is the number of the prediction generated by the algorithm, and N_(1,2,3 . . .) , if present, represent specific exons that may have been manually edited during analysis (See Example V). Alternatively, the polynucleotide fragments in column 2 may refer to assemblages of exons brought together by an “exon-stretching” algorithm. For example, a polynucleotide sequence identified as FLXXXXXX_gAAAAA_gBBBBB_(—)1_N is a “stretched” sequence, with XXXXXX being the Incyte project identification number, gAAAAA being the GenBank identification number of the human genomic sequence to which the “exon-stretching” algorithm was applied, gBBBBB being the GenBank identification number or NCBI RefSeq identification number of the nearest GenBank protein homolog, and N referring to specific exons (See Example V). In instances where a RefSeq sequence was used as a protein homolog for the “exon-stretching” algorithm, a RefSeq identifier (denoted by “NM,” “NP,” or “NT”) may be used in place of the GenBank identifier (i.e., gBBBBB).

[0181] Alternatively, a prefix identifies component sequences that were hand-edited, predicted from genomic DNA sequences, or derived from a combination of sequence analysis methods. The following Table lists examples of component sequence prefixes and corresponding sequence analysis methods associated with the prefixes (see Example IV and Example V). Prefix Type of analysis and/or examples of programs GNN, Exon prediction from genomic sequences using, for example, GFG, GENSCAN (Stanford University, CA, U.S.A.) or FGENES ENST (Computer Genomics Group, The Sanger Centre, Cambridge, UK). GBI Hand-edited analysis of genomic sequences. FL Stitched or stretched genomic sequences (see Example V). INCY Full length transcript and exon prediction from mapping of EST sequences to the genome. Genomic location and EST composition data are combined to predict the exons and resulting transcript.

[0182] In some cases, Incyte cDNA coverage redundant with the sequence coverage shown in Table 4 was obtained to confirm the final consensus polynucleotide sequence, but the relevant Incyte cDNA identification numbers are not shown.

[0183] Table 5 shows the representative cDNA libraries for those full length polynucleotide sequences which were assembled using Incyte cDNA sequences. The representative cDNA library is the Incyte cDNA library which is most frequently represented by the Incyte cDNA sequences which were used to assemble and confirm the above polynucleotide sequences. The tissues and vectors which were used to construct the cDNA libraries shown in Table 5 are described in Table 6.

[0184] The invention also encompasses KAP variants. A preferred KAP variant is one which has at least about 80%, or alternatively at least about 90%, or even at least about 95% amino acid sequence identity to the KAP amino acid sequence, and which contains at least one functional or structural characteristic of KAP.

[0185] The invention also encompasses polynucleotides which encode KAP. In a particular embodiment, the invention encompasses a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID NO:21-40, which encodes KAP. The polynucleotide sequences of SEQ ID NO:21-40, as presented in the Sequence Listing, embrace the equivalent RNA sequences, wherein occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.

[0186] The invention also encompasses a variant of a polynucleotide sequence encoding KAP. In particular, such a variant polynucleotide sequence will have at least about 70%, or alternatively at least about 85%, or even at least about 95% polynucleotide sequence identity to the polynucleotide sequence encoding KAP. A particular aspect of the invention encompasses a variant of a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID NO:21-40 which has at least about 70%, or alternatively at least about 85%, or even at least about 95% polynucleotide sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID NO:21-40. Any one of the polynucleotide variants described above can encode an amino acid sequence which contains at least one functional or structural characteristic of KAP.

[0187] In addition, or in the alternative, a polynucleotide variant of the invention is a splice variant of a polynucleotide sequence encoding KAP. A splice variant may have portions which have significant sequence identity to the polynucleotide sequence encoding KAP, but will generally have a greater or lesser number of polynucleotides due to additions or deletions of blocks of sequence arising from alternate splicing of exons during mRNA processing. A splice variant may have less than about 70%, or alternatively less than about 60%, or alternatively less than about 50% polynucleotide sequence identity to the polynucleotide sequence encoding KAP over its entire length; however, portions of the splice variant will have at least about 70%, or alternatively at least about 85%, or alternatively at least about 95%, or alternatively 100% polynucleotide sequence identity to portions of the polynucleotide sequence encoding KAP. Any one of the splice variants described above can encode an amino acid sequence which contains at least one functional or structural characteristic of KAP.

[0188] It will be appreciated by those skilled in the art that as a result of the degeneracy of the genetic code, a multitude of polynucleotide sequences encoding KAP, some bearing minimal similarity to the polynucleotide sequences of any known and naturally occurring gene, may be produced. Thus, the invention contemplates each and every possible variation of polynucleotide sequence that could be made by selecting combinations based on possible codon choices. These combinations are made in accordance with the standard triplet genetic code as applied to the polynucleotide sequence of naturally occurring KAP, and all such variations are to be considered as being specifically disclosed.

[0189] Although nucleotide sequences which encode KAP and its variants are generally capable of hybridizing to the nucleotide sequence of the naturally occurring KAP under appropriately selected conditions of stringency, it may be advantageous to produce nucleotide sequences encoding KAP or its derivatives possessing a substantially different codon usage, e.g., inclusion of non-naturally occurring codons. Codons may be selected to increase the rate at which expression of the peptide occurs in a particular prokaryotic or eukaryotic host in accordance with the frequency with which particular codons are utilized by the host. Other reasons for substantially altering the nucleotide sequence encoding KAP and its derivatives without altering the encoded amino acid sequences include the production of RNA transcripts having more desirable properties, such as a greater half-life, than transcripts produced from the naturally occurring sequence.

[0190] The invention also encompasses production of DNA sequences which encode KAP and KAP derivatives, or fragments thereof, entirely by synthetic chemistry. After production, the synthetic sequence may be inserted into any of the many available expression vectors and cell systems using reagents well known in the art. Moreover, synthetic chemistry may be used to introduce mutations into a sequence encoding KAP or any fragment thereof.

[0191] Also encompassed by the invention are polynucleotide sequences that are capable of hybridizing to the claimed polynucleotide sequences, and, in particular, to those shown in SEQ ID NO:21-40 and fragments thereof under various conditions of stringency. (See, e.g., Wahl, G. M. and S. L. Berger (1987) Methods Enzymol. 152:399-407; Kimmel, A. R. (1987) Methods Enzymol. 152:507-511.) Hybridization conditions, including annealing and wash conditions, are described in “Definitions.”

[0192] Methods for DNA sequencing are well known in the art and may be used to practice any of the embodiments of the invention. The methods may employ such enzymes as the Klenow fragment of DNA polymerase I, SEQUENASE (US Biochemical, Cleveland Ohio), Taq polymerase (Applied Biosystems), thermostable T7 polymerase (Amersham Pharmacia Biotech, Piscataway N.J.), or combinations of polymerases and proofreading exonucleases such as those found in the ELONGASE amplification system (Life Technologies, Gaithersburg Md.). Preferably, sequence preparation is automated with machines such as the MICROLAB 2200 liquid transfer system (Hamilton, Reno Nev.), PTC200 thermal cycler (MJ Research, Watertown Mass.) and ABI CATALYST 800 thermal cycler (Applied Biosystems). Sequencing is then carried out using either the ABI 373 or 377 DNA sequencing system (Applied Biosystems), the MEGABACE 1000 DNA sequencing system (Molecular Dynamics, Sunnyvale Calif.), or other systems known in the art. The resulting sequences are analyzed using a variety of algorithms which are well known in the art. (See, e.g., Ausubel, F. M. (1997) Short Protocols in Molecular Biology, John Wiley & Sons, New York N.Y., unit 7.7; Meyers, R. A. (1995) Molecular Biology and Biotechnology, Wiley VCH, New York N.Y., pp. 856-853.)

[0193] The nucleic acid sequences encoding KAP may be extended utilizing a partial nucleotide sequence and employing various PCR-based methods known in the art to detect upstream sequences, such as promoters and regulatory elements. For example, one method which may be employed, restriction-site PCR, uses universal and nested primers to amplify unknown sequence from genomic DNA within a cloning vector. (See, e.g., Sarkar, G. (1993) PCR Methods Applic. 2:318-322.) Another method, inverse PCR, uses primers that extend in divergent directions to amplify unknown sequence from a circularized template. The template is derived from restriction fragments comprising a known genomic locus and surrounding sequences. (See, e.g., Triglia, T. et al. (1988) Nucleic Acids Res. 16:8186.) A third method, capture PCR, involves PCR amplification of DNA fragments adjacent to known sequences in human and yeast artificial chromosome DNA. (See, e.g., Lagerstrom, M. et al. (1991) PCR Methods Applic. 1: 111-119.) In this method, multiple restriction enzyme digestions and ligations may be used to insert an engineered double-stranded sequence into a region of unknown sequence before performing PCR. Other methods which may be used to retrieve unknown sequences are known in the art. (See, e.g., Parker, J. D. et al. (1991) Nucleic Acids Res. 19:3055-3060). Additionally, one may use PCR, nested primers, and PROMOTERFINDER libraries (Clontech, Palo Alto Calif.) to walk genomic DNA. This procedure avoids the need to screen libraries and is useful in finding intron/exon junctions. For all PCR-based methods, primers may be designed using commercially available software, such as OLIGO 4.06 primer analysis software (National Biosciences, Plymouth Minn.) or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the template at temperatures of about 68° C. to 72° C.

[0194] When screening for full length cDNAs, it is preferable to use libraries that have been size-selected to include larger cDNAs. In addition, random-primed libraries, which often include sequences containing the 5′ regions of genes, are preferable for situations in which an oligo d(T) library does not yield a full-length cDNA. Genomic libraries may be useful for extension of sequence into 5′ non-transcribed regulatory regions.

[0195] Capillary electrophoresis systems which are commercially available may be used to analyze the size or confirm the nucleotide sequence of sequencing or PCR products. In particular, capillary sequencing may employ flowable polymers for electrophoretic separation, four different nucleotide-specific, laser-stimulated fluorescent dyes, and a charge coupled device camera for detection of the emitted wavelengths. Output/light intensity may be converted to electrical signal using appropriate software (e.g., GENOTYPER and SEQUENCE NAVIGATOR, Applied Biosystems), and the entire process from loading of samples to computer analysis and electronic data display may be computer controlled. Capillary electrophoresis is especially preferable for sequencing small DNA fragments which may be present in limited amounts in a particular sample.

[0196] In another embodiment of the invention, polynucleotide sequences or fragments thereof which encode KAP may be cloned in recombinant DNA molecules that direct expression of KAP, or fragments or functional equivalents thereof, in appropriate host cells. Due to the inherent degeneracy of the genetic code, other DNA sequences which encode substantially the same or a functionally equivalent amino acid sequence may be produced and used to express KAP.

[0197] The nucleotide sequences of the present invention can be engineered using methods generally known in the art in order to alter KAP-encoding sequences for a variety of purposes including, but not limited to, modification of the cloning, processing, and/or expression of the gene product. DNA shuffling by random fragmentation and PCR reassembly of gene fragments and synthetic oligonucleotides may be used to engineer the nucleotide sequences. For example, oligonucleotide-mediated site-directed mutagenesis may be used to introduce mutations that create new restriction sites, alter glycosylation patterns, change codon preference, produce splice variants, and so forth.

[0198] The nucleotides of the present invention may be subjected to DNA shuffling techniques such as MOLECULARBREEDING (Maxygen Inc., Santa Clara Calif.; described in U.S. Pat. No. 5,837,458; Chang, C. -C. et al. (1999) Nat. Biotechnol. 17:793-797; Christians, F. C. et al. (1999) Nat Biotechnol. 17:259-264; and Crameri, A. et al. (1996) Nat. Biotechnol. 14:315-319) to alter or improve the biological properties of KAP, such as its biological or enzymatic activity or its ability to bind to other molecules or compounds. DNA shuffling is a process by which a library of gene variants is produced using PCR-mediated recombination of gene fragments. The library is then subjected to selection or screening procedures that identify those gene variants with the desired properties. These preferred variants may then be pooled and further subjected to recursive rounds of DNA shuffling and selection/screening. Thus, genetic diversity is created through “artificial” breeding and rapid molecular evolution. For example, fragments of a single gene containing random point mutations may be recombined, screened, and then reshuffled until the desired properties are optimized. Alternatively, fragments of a given gene may be recombined with fragments of homologous genes in the same gene family, either from the same or different species, thereby maximizing the genetic diversity of multiple naturally occurring genes in a directed and controllable manner.

[0199] In another embodiment, sequences encoding KAP may be synthesized, in whole or in part, using chemical methods well known in the art. (See, e.g., Caruthers, M. H. et al. (1980) Nucleic Acids Symp. Ser. 7:215-223; and Horn, T. et al. (1980) Nucleic Acids Symp. Ser. 7:225-232.) Alternatively, KAP itself or a fragment thereof may be synthesized using chemical methods. For example, peptide synthesis can be performed using various solution-phase or solid-phase techniques. (See, e.g., Creighton, T. (1984) Proteins, Structures and Molecular Properties, W H Freeman, New York N.Y., pp. 5560; and Roberge, J. Y. et al. (1995) Science 269:202-204.) Automated synthesis may be achieved using the ABI 431A peptide synthesizer (Applied Biosystems). Additionally, the amino acid sequence of KAP, or any part thereof, may be altered during direct synthesis and/or combined with sequences from other proteins, or any part thereof, to produce a variant polypeptide or a polypeptide having a sequence of a naturally occurring polypeptide.

[0200] The peptide may be substantially purified by preparative high performance liquid chromatography. (See, e.g., Chiez, R. M. and F. Z. Regnier (1990) Methods Enzymol. 182:392-421.) The composition of the synthetic peptides may be confirmed by amino acid analysis or by sequencing. (See, e.g., Creighton, supra, pp. 28-53.)

[0201] In order to express a biologically active KAP, the nucleotide sequences encoding KAP or derivatives thereof may be inserted into an appropriate expression vector, i.e., a vector which contains the necessary elements for transcriptional and translational control of the inserted coding sequence in a suitable host. These elements include regulatory sequences, such as enhancers, constitutive and inducible promoters, and 5′ and 3′ untranslated regions in the vector and in polynucleotide sequences encoding KAP. Such elements may vary in their strength and specificity. Specific initiation signals may also be used to achieve more efficient translation of sequences encoding KAP. Such signals include the ATG initiation codon and adjacent sequences, e.g. the Kozak sequence. In cases where sequences encoding KAP and its initiation codon and upstream regulatory sequences are inserted into the appropriate expression vector, no additional transcriptional or translational control signals may be needed. However, in cases where only coding sequence, or a fragment thereof, is inserted, exogenous translational control signals including an in-frame ATG initiation codon should be provided by the vector. Exogenous translational elements and initiation codons may be of various origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of enhancers appropriate for the particular host cell system used. (See, e.g., Scharf, D. et al. (1994) Results Probl. Cell Differ. 20:125-162.)

[0202] Methods which are well known to those skilled in the art may be used to construct expression vectors containing sequences encoding KAP and appropriate transcriptional and translational control elements. These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. (See, e.g., Sambrook, J. et al. (1989) Molecular Cloning. A Laboratory Manual, Cold Spring Harbor Press, Plainview N.Y., ch. 4, 8, and 16-17; Ausubel, F. M. et al. (1995) Current Protocols in Molecular Biolog, John Wiley & Sons, New York N.Y., ch. 9, 13, and 16.)

[0203] A variety of expression vector/host systems may be utilized to contain and express sequences encoding KAP. These include, but are not limited to, microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid, or cosmid DNA expression vectors; yeast transformed with yeast expression vectors; insect cell systems infected with viral expression vectors (e.g., baculovirus); plant cell systems transformed with viral expression vectors (e.g., cauliflower mosaic virus, CaMV, or tobacco mosaic virus, TMV) or with bacterial expression vectors (e.g., Ti or pBR322 plasmids); or animal cell systems. (See, e.g., Sambrook, supra; Ausubel, supra; Van Heeke, G. and S. M. Schuster (1989) J. Biol. Chem. 264:5503-5509; Engelhard, E. K. et al. (1994) Proc. Natl. Acad. Sci. USA 91:3224-3227; Sandig, V. et al. (1996) Hum Gene Ther. 7:1937-1945; Takamatsu, N. (1987) EMBO J. 6:307-311; The McGraw Hill Yearbook of Science and Technology (1992) McGraw Hill, New York N.Y., pp. 191-196; Logan, J. and T. Shenk (1984) Proc. Natl. Acad. Sci. USA 81:3655-3659; and Harrington, J. J. et al. (1997) Nat Genet. 15:345-355.) Expression vectors derived from retroviruses, adenoviruses, or herpes or vaccinia viruses, or from various bacterial plasmids, may be used for delivery of nucleotide sequences to the targeted organ, tissue, or cell population. (See, e.g., Di Nicola, M. et al. (1998) Cancer Gen. Ther. 5(6):350-356; Yu, M. et al. (1993) Proc. Natl. Acad. Sci. USA 90(13):6340-6344; Buller, R. M. et al. (1985) Nature 317(6040):813-815; McGregor, D. P. et al. (1994) Mol. Immunol. 31(3):219-226; and Verma, I. M. and N. Somia (1997) Nature 389:239-242.) The invention is not limited by the host cell employed.

[0204] In bacterial systems, a number of cloning and expression vectors may be selected depending upon the use intended for polynucleotide sequences encoding KAP. For example, routine cloning, subcloning, and propagation of polynucleotide sequences encoding KAP can be achieved using a multifunctional E. coli vector such as PBLUESCRIPT (Stratagene, La Jolla Calif.) or PSPORT1 plasmid (Life Technologies). Ligation of sequences encoding KAP into the vector's multiple cloning site disrupts the lacZ gene, allowing a colorimetric screening procedure for identification of transformed bacteria containing recombinant molecules. In addition, these vectors may be useful for in vitro transcription, dideoxy sequencing, single strand rescue with helper phage, and creation of nested deletions in the cloned sequence. (See, e.g., Van Heeke, G. and S. M. Schuster (1989) J. Biol. Chem. 264:5503-5509.) When large quantities of KAP are needed, e.g. for the production of antibodies, vectors which direct high level expression of KAP may be used. For example, vectors containing the strong, inducible SP6 or T7 bacteriophage promoter may be used.

[0205] Yeast expression systems may be used for production of KAP. A number of vectors containing constitutive or inducible promoters, such as alpha factor, alcohol oxidase, and PGH promoters, may be used in the yeast Saccharomyces cerevisiae or Pichia pastoris. In addition, such vectors direct either the secretion or intracellular retention of expressed proteins and enable integration of foreign sequences into the host genome for stable propagation. (See, e.g., Ausubel, 1995, supra; Bitter, G. A. et al. (1987) Methods Enzymol. 153:516-544; and Scorer, C. A. et al. (1994) Bio/Technology 12:181-184.)

[0206] Plant systems may also be used for expression of KAP. Transcription of sequences encoding KAP may be driven by viral promoters, e.g., the 35S and 19S promoters of CaMV used alone or in combination with the omega leader sequence from TMV (Takamatsu, N. (1987) EMBO J. 6:307-311). Alternatively, plant promoters such as the small subunit of RUBISCO or heat shock promoters may be used. (See, e.g., Coruzzi, G. et al. (1984) EMBO J. 3:1671-1680; Broglie, R. et al. (1984) Science 224:838-843; and Winter, J. et al. (1991) Results Probl. Cell Differ. 17:85-105.) These constructs can be introduced into plant cells by direct DNA transformation or pathogen-mediated transfection. (See, e.g., The McGraw Hill Yearbook of Science and Technology (1992) McGraw Hill, New York N.Y., pp. 191-196.)

[0207] In mammalian cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, sequences encoding KAP may be ligated into an adenovirus transcription/translation complex consisting of the late promoter and tripartite leader sequence. Insertion in a non-essential E1 or E3 region of the viral genome may be used to obtain infective virus which expresses KAP in host cells. (See, e.g., Logan, J. and T. Shenk (1984) Proc. Natl. Acad. Sci. USA 81:3655-3659.) In addition, transcription enhancers, such as the Rous sarcoma virus (RSV) enhancer, may be used to increase expression in mammalian host cells. SV40 or EBV-based vectors may also be used for high-level protein expression.

[0208] Human artificial chromosomes (HACs) may also be employed to deliver larger fragments of DNA than can be contained in and expressed from a plasmid. HACs of about 6 kb to 10 Mb are constructed and delivered via conventional delivery methods (liposomes, polycationic amino polymers, or vesicles) for therapeutic purposes. (See, e.g., Harrington, J. J. et al. (1997) Nat. Genet. 15:345-355.)

[0209] For long term production of recombinant proteins in mammalian systems, stable expression of KAP in cell lines is preferred. For example, sequences encoding KAP can be transformed into cell lines using expression vectors which may contain viral origins of replication and/or endogenous expression elements and a selectable marker gene on the same or on a separate vector. Following the introduction of the vector, cells may be allowed to grow for about 1 to 2 days in enriched media before being switched to selective media. The purpose of the selectable marker is to confer resistance to a selective agent, and its presence allows growth and recovery of cells which successfully express the introduced sequences. Resistant clones of stably transformed cells may be propagated using tissue culture techniques appropriate to the cell type.

[0210] Any number of selection systems may be used to recover transformed cell lines. These include, but are not limited to, the herpes simplex virus thymidine kinase and adenine phosphoribosyltransferase genes, for use in tk⁻ and apr⁻ cells, respectively. (See, e.g., Wigler, M. et al. (1977) Cell 11:223-232; Lowy, I. et al. (1980) Cell.22:817-823.) Also, antimetabolite, antibiotic, or herbicide resistance can be used as the basis for selection. For example, dhfr confers resistance to methotrexate; neo confers resistance to the aminoglycosides neomycin and G-418; and als and pat confer resistance to chlorsulfuron and phosphinotricin acetyltransferase, respectively. (See, e.g., Wigler, M. et al. (1980) Proc. Natl. Acad. Sci. USA 77:3567-3570; Colbere-Garapin, F. et al. (1981) J. Mol. Biol. 150:1-14.) Additional selectable genes have been described, e.g., trpB and hisD, which alter cellular requirements for metabolites. (See, e.g., Hartan, S. C. and R. C. Mulligan (1988) Proc. Natl. Acad. Sci. USA 85:8047-8051.) Visible markers, e.g., anthocyanins, green fluorescent proteins (GFP; Clontech), β glucuronidase and its substrate β-glucuronide, or luciferase and its substrate luciferin may be used. These markers can be used not only to identify transformants, but also to quantify the amount of transient or stable protein expression attributable to a specific vector system. (See, e.g., Rhodes, C. A. (1995) Methods Mol. Biol. 55:121-131.)

[0211] Although the presence/absence of marker gene expression suggests that the gene of interest is also present, the presence and expression of the gene may need to be confirmed. For example, if the sequence encoding KAP is inserted within a marker gene sequence, transformed cells containing sequences encoding KAP can be identified by the absence of marker gene function. Alternatively, a marker gene can be placed in tandem with a sequence encoding KAP under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of the tandem gene as well.

[0212] In general, host cells that contain the nucleic acid sequence encoding KAP and that express KAP may be identified by a variety of procedures known to those of skill in the art. These procedures include, but are not limited to, DNA-DNA or DNA-RNA hybridizations, PCR amplification, and protein bioassay or immunoassay techniques which include membrane, solution, or chip based technologies for the detection and/or quantification of nucleic acid or protein sequences.

[0213] Immunological methods for detecting and measuring the expression of KAP using either specific polyclonal or monoclonal antibodies are known in the art. Examples of such techniques include enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs), and fluorescence activated cell sorting (FACS). A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering epitopes on KAP is preferred, but a competitive binding assay may be employed. These and other assays are well known in the art. (See, e.g., Hampton, R. et al. (1990) Serological Methods, a Laboratory Manual, APS Press, St. Paul Minn., Sect. IV; Coligan, J. E. et al. (1997) Current Protocols in Immunology, Greene Pub. Associates and Wiley-Interscience, New York N.Y.; and Pound, J. D. (1998) Immunochemical Protocols, Humana Press, Totowa N.J.)

[0214] A wide variety of labels and conjugation techniques are known by those skilled in the art and may be used in various nucleic acid and amino acid assays. Means for producing labeled hybridization or PCR probes for detecting sequences related to polynucleotides encoding KAP include oligolabeling, nick translation, end-labeling, or PCR amplification using a labeled nucleotide. Alternatively, the sequences encoding KAP, or any fragments thereof, may be cloned into a vector for the production of an mRNA probe. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by addition of an appropriate RNA polymerase such as T7, T3, or SP6 and labeled nucleotides. These procedures may be conducted using a variety of commercially available kits, such as those provided by Amersham Pharmacia Biotech, Promega (Madison Wis.), and US Biochemical. Suitable reporter molecules or labels which may be used for ease of detection include radionuclides, enzymes, fluorescent, chemiluminescent, or chromogenic agents, as well as substrates, cofactors, inhibitors, magnetic particles, and the like.

[0215] Host cells transformed with nucleotide sequences encoding KAP may be cultured under conditions suitable for the expression and recovery of the protein from cell culture. The protein produced by a transformed cell may be secreted or retained intracellularly depending on the sequence and/or the vector used. As will be understood by those of skill in the art, expression vectors containing polynucleotides which encode KAP may be designed to contain signal sequences which direct secretion of KAP through a prokaryotic or eukaryotic cell membrane.

[0216] In addition, a host cell strain may be chosen for its ability to modulate expression of the inserted sequences or to process the expressed protein in the desired fashion. Such modifications of the polypeptide include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation. Post-translational processing which cleaves a “prepro” or “pro” form of the protein may also be used to specify protein targeting, folding, and/or activity. Different host cells which have specific cellular machinery and characteristic mechanisms for post-translational activities (e.g., CHO, HeLa, MDCK, HEK293, and WI38) are available from the American Type Culture Collection (ATCC, Manassas Va.) and may be chosen to ensure the correct modification and processing of the foreign protein.

[0217] In another embodiment of the invention, natural, modified, or recombinant nucleic acid sequences encoding KAP may be ligated to a heterologous sequence resulting in translation of a fusion protein in any of the aforementioned host systems. For example, a chimeric KAP protein containing a heterologous moiety that can be recognized by a commercially available antibody may facilitate the screening of peptide libraries for inhibitors of KAP activity. Heterologous protein and peptide moieties may also facilitate purification of fusion proteins using commercially available affinity matrices. Such moieties include, but are not limited to, glutathione S-transferase (GST), maltose binding protein (MBP), thioredoxin (Trx), calmodulin binding peptide (CBP), ⁶-His, FLAG, c-myc, and hemagglutinin (HA). GST, MBP, Trx, CBP, and 6His enable purification of their cognate fusion proteins on immobilized glutathione, maltose, phenylarsine oxide, calmodulin, and metal-chelate resins, respectively. FLAG, c-myc, and hemagglutinin (HA) enable immunoaffinity purification of fusion proteins using commercially available monoclonal and polyclonal antibodies that specifically recognize these epitope tags. A fusion protein may also be engineered to contain a proteolytic cleavage site located between the KAP encoding sequence and the heterologous protein sequence, so that KAP may be cleaved away from the heterologous moiety following purification. Methods for fusion protein expression and purification are discussed in Ausubel (1995, supra, ch. 10). A variety of commercially available kits may also be used to facilitate expression and purification of fusion proteins.

[0218] In a further embodiment of the invention, synthesis of radiolabeled KAP may be achieved in vitro using the TNT rabbit reticulocyte lysate or wheat germ extract system (Promega). These systems couple transcription and translation of protein-coding sequences operably associated with the T7, T3, or SP6 promoters. Translation takes place in the presence of a radiolabeled amino acid precursor, for example, ³⁵S-methionine.

[0219] KAP of the present invention or fragments thereof may be used to screen for compounds that specifically bind to KAP. At least one and up to a plurality of test compounds may be screened for specific binding to KAP. Examples of test compounds include antibodies, oligonucleotides, proteins (e.g., receptors), or small molecules.

[0220] In one embodiment, the compound thus identified is closely related to the natural ligand of KAP, e.g., a ligand or fragment thereof, a natural substrate, a structural or functional mimetic, or a natural binding partner. (See, e.g., Coligan, J. E. et al. (1991) Current Protocols in Immunology 1(2):Chapter 5.) Similarly, the compound can be closely related to the natural receptor to which KAP binds, or to at least a fragment of the receptor, e.g., the ligand binding site. In either case, the compound can be rationally designed using known techniques. In one embodiment, screening for these compounds involves producing appropriate cells which express KAP, either as a secreted protein or on the cell membrane. Preferred cells include cells from mammals, yeast, Drosophila, or E. coli. Cells expressing KAP or cell membrane fractions which contain KAP are then contacted with a test compound and binding, stimulation, or inhibition of activity of either KAP or the compound is analyzed.

[0221] An assay may simply test binding of a test compound to the polypeptide, wherein binding is detected by a fluorophore, radioisotope, enzyme conjugate, or other detectable label. For example, the assay may comprise the steps of combining at least one test compound with KAP, either in solution or affixed to a solid support, and detecting the binding of KAP to the compound. Alternatively, the assay may detect or measure binding of a test compound in the presence of a labeled competitor. Additionally, the assay may be carried out using cell-free preparations, chemical libraries, or natural product mixtures, and the test compound(s) may be free in solution or affixed to a solid support.

[0222] KAP of the present invention or fragments thereof may be used to screen for compounds that modulate the activity of KAP. Such compounds may include agonists, antagonists, or partial or inverse agonists. In one embodiment, an assay is performed under conditions permissive for KAP activity, wherein KAP is combined with at least one test compound, and the activity of KAP in the presence of a test compound is compared with the activity of KAP in the absence of the test compound. A change in the activity of KAP in the presence of the test compound is indicative of a compound that modulates the activity of KAP. Alternatively, a test compound is combined with an in vitro or cell-free system comprising KAP under conditions suitable for KAP activity, and the assay is performed. In either of these assays, a test compound which modulates the activity of KAP may do so indirectly and need not come in direct contact with the test compound. At least one and up to a plurality of test compounds may be screened.

[0223] In another embodiment, polynucleotides encoding KAP or their mammalian homologs may be “knocked out” in an animal model system using homologous recombination in embryonic stem (ES) cells. Such techniques are well known in the art and are useful for the generation of animal models of human disease. (See, e.g., U.S. Pat. No. 5,175,383 and U.S. Pat. No. 5,767,337.) For example, mouse ES cells, such as the mouse 129/SvJ cell line, are derived from the early mouse embryo and grown in culture. The ES cells are transformed with a vector containing the gene of interest disrupted by a marker gene, e.g., the neomycin phosphotransferase gene (neo; Capecchi, M. R. (1989) Science 244:1288-1292). The vector integrates into the corresponding region of the host genome by homologous recombination. Alternatively, homologous recombination takes place using the Cre-loxP system to knockout a gene of interest in a tissue- or developmental stage-specific manner (Marth, J. D. (1996) Clin. Invest. 97:1999-2002; Wagner, K. U. et al. (1997) Nucleic Acids Res. 25:4323-4330). Transformed ES cells are identified and microinjected into mouse cell blastocysts such as those from the C57BL/6 mouse strain. The blastocysts are surgically transferred to pseudopregnant dams, and the resulting chimeric progeny are genotyped and bred to produce heterozygous or homozygous strains. Transgenic animals thus generated may be tested with potential therapeutic or toxic agents.

[0224] Polynucleotides encoding KAP may also be manipulated in vitro in ES cells derived from human blastocysts. Human ES cells have the potential to differentiate into at least eight separate cell lineages including endoderm, mesoderm, and ectodermal cell types. These cell lineages differentiate into, for example, neural cells, hematopoietic lineages, and cardiomyocytes (Thomson, J. A. et al. (1998) Science 282:1145-1147).

[0225] Polynucleotides encoding KAP can also be used to create “knockin” humanized animals (pigs) or transgenic animals (mice or rats) to model human disease. With knockin technology, a region of a polynucleotide encoding KAP is injected into animal ES cells, and the injected sequence integrates into the animal cell genome. Transformed cells are injected into blastulae, and the blastulae are implanted as described above. Transgenic progeny or inbred lines are studied and treated with potential pharmaceutical agents to obtain information on treatment of a human disease. Alternatively, a mammal inbred to overexpress KAP, e.g., by secreting KAP in its milk, may also serve as a convenient source of that protein (Janne, J. et al. (1998) Biotechnol. Annu. Rev. 4:55-74).

Therapeutics

[0226] Chemical and structural similarity, e.g., in the context of sequences and motifs, exists between regions of KAP and kinases and phosphatases. In addition, examples of tissues expressing KAP can be found in Table 6. Therefore, KAP appears to play a role in cardiovascular diseases, immune system disorders, neurological disorders, disorders affecting growth and development, lipid disorders, cell proliferative disorders, and cancers. In the treatment of disorders associated with increased KAP expression or activity, it is desirable to decrease the expression or activity of KAP. In the treatment of disorders associated with decreased KAP expression or activity, it is desirable to increase the expression or activity of KAP.

[0227] Therefore, in one embodiment, KAP or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of KAP. Examples of such disorders include, but are not limited to, a cardiovascular disorder such as arteriovenous fistula, atherosclerosis, hypertension, vasculitis, Raynaud's disease, aneurysms, arterial dissections, varicose veins, thrombophlebitis and phlebothrombosis, vascular tumors,and complications of thrombolysis, balloon angioplasty, vascular replacement, and coronary artery bypass graft: surgery, congestive heart failure, ischemic heart disease, angina pectoris, myocardial infarction, hypertensive heart disease, degenerative valvular heart disease, calcific aortic valve stenosis, congenitally bicuspid aortic valve, mitral annular calcification, mitral valve prolapse, rheumatic fever and rheumatic heart disease, infective endocarditis, nonbacterial thrombotic endocarditis, endocarditis of systemic lupus erythematosus, carcinoid heart disease, cardiomyopathy, myocarditis, pericarditis, neoplastic heart disease, congenital heart disease, and complications of cardiac transplantation, congenital lung anomalies, atelectasis, pulmonary congestion and edema, pulmonary embolism, pulmonary hemorrhage, pulmonary infarction, pulmonary hypertension, vascular sclerosis, obstructive pulmonary disease, restrictive pulmonary disease, chronic obstructive pulmonary disease, emphysema, chronic bronchitis, bronchial asthma, bronchiectasis, bacterial pneumonia, viral and mycoplasmal pneumonia, lung abscess, pulmonary tuberculosis, diffuse interstitial diseases, pneumoconioses, sarcoidosis, idiopathic pulmonary fibrosis, desquamative interstitial pneumonitis, hypersensitivity pneumonitis, pulmonary eosinophilia bronchiolitis obliterans-organizing pneumonia, diffuse pulmonary hemorrhage syndromes, Goodpasture's syndromes, idiopathic pulmonary hemosiderosis, pulmonary involvement in collagen-vascular disorders, pulmonary alveolar proteinosis, lung tumors, inflammatory and noninflammatory pleural efflusions, pneumothorax, pleural tumors, drug-induced lung disease, radiation-induced lung disease, and complications of lung transplantation; an immune disorder such as acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy (APECED), bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and hehninthic infections, and trauma; a neurological disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease, prion diseases including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorders of the central nervous system including Down syndrome, cerebral palsy, neuroskeletal disorders, autonomic nervous system disorders, cranial nerve disorders, spinal cord diseases, muscular dystrophy and other neuromuscular disorders, peripheral nervous system disorders, dermatomyositis and polymyositis, inherited, metabolic, endocrine, and toxic myopathies, myasthenia gravis, periodic paralysis, mental disorders including mood, anxiety, and schizophrenic disorders, seasonal affective disorder (SAD), akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, Tourette's disorder, progressive supranuclear palsy, corticobasal degeneration, and familial frontotemporal dementia; a growth and developmental disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCID), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, renal tubular acidosis, anemia, Cushing's syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy, epilepsy, gonadal dysgenesis, WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas, hereditary neuropathies such as Charcot-Marie-Tooth disease and neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders such as Syndenham's chorea and cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital glaucoma, cataract, and sensorineural hearing loss; a lipid disorder such as fatty liver, cholestasis, primary biliary cirrhosis, carnitine deficiency, carnitine palnitoyltransferase deficiency, myoadenylate deaminase deficiency, hypertriglyceridemia, lipid storage disorders such Fabry's disease, Gaucher's disease, Niemann-Pick's disease, metachromatic leukodystrophy, adrenoleukodystrophy, GM₂ gangliosidosis, and ceroid lipofuscinosis, abetalipoproteinemia, Tangier disease, hyperlipoproteinemia, diabetes mellitus, lipodystrophy, lipomatoses, acute panniculitis, disseminated fat necrosis, adiposis dolorosa, lipoid adrenal hyperplasia, minimal change disease, lipomas, atherosclerosis, hypercholesterolemia, hypercholesterolemia with hypertriglyceridemia, primary hypoalphalipoproteinemia, hypothyroidism, renal disease, liver disease, lecithin:cholesterol acyltransferase deficiency, cerebrotendinous xanthomatosis, sitosterolemia, hypocholesterolemia, Tay-Sachs disease, Sandhoff's disease, hyperlipidemia, hyperlipemia, lipid myopathies, and obesity; and a cell proliferative disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, uterus, leukemias such as multiple myeloma, and lymphomas such as Hodgkin's disease.

[0228] In another embodiment, a vector capable of expressing KAP or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of KAP including, but not limited to, those described above.

[0229] In a further embodiment, a composition comprising a substantially purified KAP in conjunction with a suitable pharmaceutical carrier may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of KAP including, but not limited to, those provided above.

[0230] In still another embodiment, an agonist which modulates the activity of KAP may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of KAP including, but not limited to, those listed above.

[0231] In a further embodiment, an antagonist of KAP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of KAP. Examples of such disorders include, but are not limited to, those cardiovascular diseases, immune system disorders, neurological disorders, disorders affecting growth and development, lipid disorders, cell proliferative disorders, and cancers described above. In one aspect, an antibody which specifically binds KAP may be used directly as an antagonist or indirectly as a targeting or delivery mechanism for bringing a pharmaceutical agent to cells or tissues which express KAP.

[0232] In an additional embodiment, a vector expressing the complement of the polynucleotide encoding KAP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of KAP including, but not limited to, those described above.

[0233] In other embodiments, any of the proteins, antagonists, antibodies, agonists, complementary sequences, or vectors of the invention may be administered in combination with other appropriate therapeutic agents. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.

[0234] An antagonist of KAP may be produced using methods which are generally known in the art. In particular, purified KAP may be used to produce antibodies or to screen libraries of pharmaceutical agents to identify those which specifically bind KAP. Antibodies to KAP may also be generated using methods that are well known in the art. Such antibodies may include, but are not limited to, polyclonal, monoclonal, chimeric, and single chain antibodies, Fab fragments, and fragments produced by a Fab expression library. Neutralizing antibodies (i.e., those which inhibit dimer formation) are generally preferred for therapeutic use.

[0235] For the production of antibodies, various hosts including goats, rabbits, rats, mice, humans, and others may be immunized by injection with KAP or with any fragment or oligopeptide thereof which has immunogenic properties. Depending on the host species, various adjuvants may be used to increase immunological response. Such adjuvants include, but are not limited to, Freund's, mineral gels such as aluminum hydroxide, and surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, KLK, and dinitrophenol. Among adjuvants used in humans, BCG (bacilli Calmette-Guerin) and Corynebacterium parvum are especially preferable.

[0236] It is preferred that the oligopeptides, peptides, or fragments used to induce antibodies to KAP have an amino acid sequence consisting of at least about 5 amino acids, and generally will consist of at least about 10 amino acids. It is also preferable that these oligopeptides, peptides, or fragments are identical to a portion of the amino acid sequence of the natural protein. Short stretches of KAP amino acids may be fused with those of another protein, such as KLH, and antibodies to the chimeric molecule may be produced.

[0237] Monoclonal antibodies to KAP may be prepared using any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique, the human B-cell hybridoma technique, and the EBV-hybridoma technique. (See, e.g., Kohler, G. et al. (1975) Nature 256:495-497; Kozbor, D. et al. (1985) J. Immunol. Methods 81:31-42; Cote, R. J. et al. (1983) Proc. Natl. Acad. Sci. USA 80:2026-2030; and Cole, S. P. et al. (1984) Mol. Cell Biol. 62:109-120.)

[0238] In addition, techniques developed for the production of “chimeric antibodies,” such as the splicing of mouse antibody genes to human antibody genes to obtain a molecule with appropriate antigen specificity and biological activity, can be used. (See, e.g., Morrison, S. L. et al. (1984) Proc. Natl. Acad. Sci. USA 81:6851-6855; Neuberger, M. S. et al. (1984) Nature 312:604-608; and Takeda, S. et al. (1985) Nature 314:452-454.) Alternatively, techniques described for the production of single chain antibodies may be adapted, using methods known in the art, to produce KAP-specific single chain antibodies. Antibodies with related specificity, but of distinct idiotypic composition, may be generated by chain shuffling from random combinatorial immunoglobulin libraries. (See, e.g., Burton, D. R. (1991) Proc. Natl. Acad. Sci. USA 88:10134-10137.)

[0239] Antibodies may also be produced by inducing in vivo production in the lymphocyte population or by screening immunoglobulin libraries or panels of highly specific binding reagents as disclosed in the literature. (See, e.g., Orlandi, R. et al. (1989) Proc. Natl. Acad. Sci. USA 86:3833-3837; Winter, G. et al. (1991) Nature 349:293-299.)

[0240] Antibody fragments which contain specific binding sites for KAP may also be generated. For example, such fragments include, but are not limited to, F(ab′)₂ fragments produced by pepsin digestion of the antibody molecule and Fab fragments generated by reducing the disulfide bridges of the F(ab′)2 fragments. Alternatively, Fab expression libraries may be constructed to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity. (See, e.g., Huse, W. D. et al. (1989) Science 246:1275-1281.)

[0241] Various immunoassays may be used for screening to identify antibodies having the desired specificity. Numerous protocols for competitive binding or immunoradiometric assays using either polyclonal or monoclonal antibodies with established specificities are well known in the art. Such immunoassays typically involve the measurement of complex formation between KAP and its specific antibody. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering KAP epitopes is generally used, but a competitive binding assay may also be employed (Pound, supra).

[0242] Various methods such as Scatchard analysis in conjunction with radioimmunoassay techniques may be used to assess the affinity of antibodies for KAP. Affinity is expressed as an association constant, K_(a), which is defined as the molar concentration of KAP-antibody complex divided by the molar concentrations of free antigen and free antibody under equilibrium conditions. The K_(a) determined for a preparation of polyclonal antibodies, which are heterogeneous in their affinities for multiple KAP epitopes, represents the average affinity, or avidity, of the antibodies for KAP. The K_(a) determined for a preparation of monoclonal antibodies, which are monospecific for a particular KAP epitope, represents a true measure of affinity. High-affinity antibody preparations with K_(a) ranging from about 10⁹ to 10¹² L/mole are preferred for use in immunoassays in which the KAP-antibody complex must withstand rigorous manipulations. Low-affinity antibody preparations with K_(a) ranging from about 10⁶ to 10⁷ L/mole are preferred for use in immunopurification and similar procedures which ultimately require dissociation of KAP, preferably in active form, from the antibody (Catty, D. (1988) Antibodies, Volume I: A Practical Approach, IRL Press, Washington DC; Liddell, J. E. and A. Cryer (1991) A Practical Guide to Monoclonal Antibodies, John Wiley & Sons, New York N.Y.).

[0243] The titer and avidity of polyclonal antibody preparations may be further evaluated to determine the quality and suitability of such preparations for certain downstream applications. For example, a polyclonal antibody preparation containing at least 1-2 mg specific antibody/ml, preferably 5-10 mg specific antibody/ml, is generally employed in procedures requiring precipitation of KAP-antibody complexes. Procedures for evaluating antibody specificity, titer, and avidity, and guidelines for antibody quality and usage in various applications, are generally available. (See, e.g., Catty, supra, and Coligan et al. supra.)

[0244] In another embodiment of the invention, the polynucleotides encoding KAP, or any fragment or complement thereof, may be used for therapeutic purposes. In one aspect, modifications of gene expression can be achieved by designing complementary sequences or antisense molecules (DNA, RNA, PNA, or modified oligonucleotides) to the coding or regulatory regions of the gene encoding KAP. Such technology is well known in the art, and antisense oligonucleotides or larger fragments can be designed from various locations along the coding or control regions of sequences encoding KAP. (See, e.g., Agrawal, S., ed. (1996) Antisense Therapeutics, Humana Press Inc., Totawa N.J.)

[0245] In therapeutic use, any gene delivery system suitable for introduction of the antisense sequences into appropriate target cells can be used. Antisense sequences can be delivered intracellularly in the form of an expression plasmid which, upon transcription, produces a sequence complementary to at least a portion of the cellular sequence encoding the target protein. (See, e.g., Slater, J. E. et al. (1998) J. Allergy Clin. Immunol. 102(3):469-475; and Scanlon, K. J. et al. (1995) 9(13): 1288-1296.) Antisense sequences can also be introduced intracellularly through the use of viral vectors, such as retrovirus and adeno-associated virus vectors. (See, e.g., Miller, A. D. (1990) Blood 76:271; Ausubel, supra; Uckert, W. and W. Walther (1994) Pharmacol. Ther. 63(3):323-347.) Other gene delivery mechanisms include liposome-derived systems, artificial viral envelopes, and other systems known in the art. (See, e.g., Rossi, J. J. (1995) Br. Med. Bull. 51(1):217-225; Boado, R. J. et al. (1998) J. Pharm. Sci. 87(11):1308-1315; and Morris, M. C. et al. (1997) Nucleic Acids Res. 25(14):2730-2736.)

[0246] In another embodiment of the invention, polynucleotides encoding KAP may be used for somatic or germline gene therapy. Gene therapy may be performed to (i) correct a genetic deficiency (e.g., in the cases of severe combined immunodeficiency (SCID)-X1 disease characterized by X-linked inheritance (Cavazzana-Calvo, M. et al. (2000) Science 288:669-672), severe combined immunodeficiency syndrome associated with an inherited adenosine deaminase (ADA) deficiency (Blaese, R. M. et al. (1995) Science 270:475-480; Bordignon, C. et al. (1995) Science 270:470-475), cystic fibrosis (Zabner, J. et al. (1993) Cell 75:207-216; Crystal, R. G. et al. (1995) Hum. Gene Therapy 6:643-666; Crystal, R. G. et al. (1995) Hum. Gene Therapy 6:667-703), thalassamias, familial hypercholesterolemia, and hemophilia resulting from Factor VIII or Factor IX deficiencies (Crystal, R. G. (1995) Science 270:404-410; Verma, I. M. and N. Somia (1997) Nature 389:239-242)), (ii) express a conditionally lethal gene product (e.g., in the case of cancers which result from unregulated cell proliferation), or (iii) express a protein which affords protection against intracellular parasites (e.g., against human retroviruses, such as human immunodeficiency virus (HIV) (Baltimore, D. (1988) Nature 335:395-396; Poeschla, E. et al. (1996) Proc. Natl. Acad. Sci. USA 93:11395-11399), hepatitis B or C virus (HBV, HCV); fungal parasites, such as Candida albicans and Paracoccidioides brasiliensis; and protozoan parasites such as Plasmodium falciparum and Trypanosoma cruzi). In the case where a genetic deficiency in KAP expression or regulation causes disease, the expression of KAP from an appropriate population of transduced cells may alleviate the clinical manifestations caused by the genetic deficiency.

[0247] In a further embodiment of the invention, diseases or disorders caused by deficiencies in KAP are treated by constructing mammalian expression vectors encoding KAP and introducing these vectors by mechanical means into KAP-deficient cells. Mechanical transfer technologies for use with cells in vivo or ex vitro include (i) direct DNA microinjection into individual cells, (ii) ballistic gold particle delivery, (ii) liposome-mediated transfection, (iv) receptor-mediated gene transfer, and (v) the use of DNA transposons (Morgan, R. A. and W. F. Anderson (1993) Annu. Rev. Biochem 62:191-217; Ivics, Z. (1997) Cell 91:501-510; Boulay, J -L. and IL Récipon (1998) Curr. Opin. Biotechnol. 9:445-450).

[0248] Expression vectors that may be effective for the expression of KAP include, but are not limited to, the PCDNA 3.1, EPITAG, PRCCMV2, PREP, PVAX, PCR2-TOPOTA vectors (Invitrogen, Carlsbad Calif.), PCMV-SCRIPT, PCMV-TAG, PEGSHIPERV (Stratagene, La Jolla Calif.), and PTET-OFF, PTET-ON, PTRE2, PTRE2-LUC, PTK-HYG (Clontech, Palo Alto Calif.). KAP may be expressed using (i) a constitutively active promoter, (e.g., from cytomegalovirus (CMV), Rous sarcoma virus (RSV), SV40 virus, thymidine kinase (TK), or β-actin genes), (ii) an inducible promoter (e.g., the tetracycline-regulated promoter (Gossen, M. and H. Bujard (1992) Proc. Natl. Acad. Sci. USA 89:5547-5551; Gossen, M. et al. (1995) Science 268:1766-1769; Rossi, F. M. V. and H. M. Blau (1998) Curr. Opin. Biotechnol. 9:451-456), commercially available in the T-REX plasmid (Invitrogen)); the ecdysone-inducible promoter (available in the plasmids PVGRXR and PIND; Invitrogen); the FK506/rapamycin inducible promoter; or the RU486/mifepristone inducible promoter (Rossi, F. M. V. and H. M. Blau, supra)), or (iii) a tissue-specific promoter or the native promoter of the endogenous gene encoding KAP from a normal individual.

[0249] Commercially available liposome transformation kits (e.g., the PERFECT LIPID TRANSFECTION KIT, available from Invitrogen) allow one with ordinary skill in the art to deliver polynucleotides to target cells in culture and require minimal effort to optimize experimental parameters. In the alternative, transformation is performed using the calcium phosphate method (Graham, F. L. and A. J. Eb (1973) Virology 52:456-467), or by electroporation (Neumann, E. et al. (1982) EMBO J. 1:841-845). The introduction of DNA to primary cells requires modification of these standardized mammalian transfection protocols.

[0250] In another embodiment of the invention, diseases or disorders caused by genetic defects with respect to KAP expression are treated by constructing a retrovirus vector consisting of (i) the polynucleotide encoding KAP under the control of an independent promoter or the retrovirus long terminal repeat (LTR) promoter, (ii) appropriate RNA packaging signals, and (iii) a Rev-responsive element (RRE) along with additional retrovirms cis-acting RNA sequences and coding sequences required for efficient vector propagation. Retrovirus vectors (e.g., PFB and PFBNEO) are commercially available (Stratagene) and are based on published data (Riviere, I. et al. (1995) Proc. Natl. Acad. Sci. USA 92:6733-6737), incorporated by reference herein. The vector is propagated in an appropriate vector producing cell line (VPCL) that expresses an envelope gene with a tropism for receptors on the target cells or a promiscuous envelope protein such as VSVg (Armentano, D. et al. (1987) J. Virol. 61:1647-1650; Bender, M. A. et al. (1987) J. Virol. 61:1639-1646; Adam, M. A. and A. D. Miller (1988) J. Virol. 62:3802-3806; Dull, T. et al. (1998) J. Virol. 72:8463-8471; Zufferey R. et al. (1998) 3. Virol. 72:9873-9880). U.S. Pat. No. 5,910,434 to Rigg (“Method for obtaining retrovirus packaging cell lines producing high transducing efficiency retroviral supernatant”) discloses a method for obtaining retrovirus packaging cell lines and is hereby incorporated by reference. Propagation of retrovirus vectors, transduction of a population of cells (e.g., CD4⁺T-cells), and the return of transduced cells to a patient are procedures well known to persons skilled in the art of gene therapy and have been well documented (Ranga, U. et al. (1997) J. Virol. 71:7020-7029; Bauer, G. et al. (1997) Blood 89:2259-2267; Bonyhadi, M. L. (1997) J. Virol. 71:4707-4716; Ranga, U. et al. (1998) Proc. Natl. Acad. Sci. USA 95:1201-1206; Su, L. (1997) Blood 89:2283-2290).

[0251] In the alternative, an adenovirus-based gene therapy delivery system is used to deliver polynucleotides encoding KAP to cells which have one or more genetic abnormalities with respect to the expression of KAP. The construction and packaging of adenovirus-based vectors are well known to those with ordinary skill in the art. Replication defective adenovirus vectors have proven to be versatile for importing genes encoding immunoregulatory proteins into intact islets in the pancreas (Csete, M. E. et al. (1995) Transplantation 27:263-268). Potentially useful adenoviral vectors are described in U.S. Pat. No. 5,707,618 to Armentano (“Adenovirus vectors for gene therapy”), hereby incorporated by reference. For adenoviral vectors, see also Antinozzi, P. A. et al. (1999) Annu. Rev. Nutr. 19:511-544 and Verma, I. M. and N. Somia (1997) Nature 18:389:239-242, both incorporated by reference herein.

[0252] In another alternative, a herpes-based, gene therapy delivery system is used to deliver polynucleotides encoding KAP to target cells which have one or more genetic abnormalities with respect to the expression of KAP. The use of herpes simplex virus (HSV)-based vectors may be especially valuable for introducing KAP to cells of the central nervous system, for which HSV has a tropism. The construction and packaging of herpes-based vectors are well known to those with ordinary skill in the art. A replication-competent herpes simplex virus (HSV) type 1-based vector has been used to deliver a reporter gene to the eyes of primates (Liu, X. et al. (1999) Exp. Eye Res. 169:385-395). The construction of a HSV-1 virus vector has also been disclosed in detail in U.S. Pat. No. 5,804,413 to DeLuca (“Herpes simplex virus strans for gene transfer”), which is hereby incorporated by reference. U.S. Pat. No. 5,804,413 teaches the use of recombinant HSV d92 which consists of a genome containing at least one exogenous gene to be transferred to a cell under the control of the appropriate promoter for purposes including human gene therapy. Also taught by this patent are the construction and use of recombinant HSV strains deleted for ICP4, ICP27 and ICP22. For HSV vectors, see also Goins, W. F. et al. (1999) J. Virol. 73:519-532 and Xu, H. et al. (1994) Dev. Biol. 163:152-161, hereby incorporated by reference. The manipulation of cloned herpesvirus sequences, the generation of recombinant virus following the transfection of multiple plasmids containing different segments of the large herpesvirus genomes, the growth and propagation of herpesvirus, and the infection of cells with herpesvirus are techniques well known to those of ordinary skill in the art.

[0253] In another alternative, an alphavirus (positive, single-stranded RNA virus) vector is used to deliver polynucleotides encoding KAP to target cells. The biology of the prototypic alphavirus, Semliki Forest Virus (SFV), has been studied extensively and gene transfer vectors have been based on the SFV genome (Garoff, H. and K. -J. Li (1998) Curr. Opin. Biotechnol. 9:464-469). During alphavirus RNA replication, a subgenomic RNA is generated that normally encodes the viral capsid proteins. This subgenomic RNA replicates to higher levels than the full length genomic RNA, resulting in the overproduction of capsid proteins relative to the viral proteins with enzymatic activity (e.g., protease and polymerase). Similarly, inserting the coding sequence for KAP into the alphavirus genome in place of the capsid-coding region results in the production of a large number of KAP-coding RNAs and the synthesis of high levels of KAP in vector transduced cells. While alphavirus infection is typically associated with cell lysis within a few days, the ability to establish a persistent infection in hamster normal kidney cells (BHK-21) with a variant of Sindbis virus (SIN) indicates that the lytic replication of alphaviruses can be altered to suit the needs of the gene therapy application (Dryga, S. A. et al. (1997) Virology 228:74-83). The wide host range of alphaviruses will allow the introduction of KAP into a variety of cell types. The specific transduction of a subset of cells in a population may require the sorting of cells prior to transduction. The methods of manipulating infectious cDNA clones of alphaviruses, performing alphavirus cDNA and RNA transfections, and performing alphavirus infections, are well known to those with ordinary skill in the art.

[0254] Oligonucleotides derived from the transcription initiation site, e.g., between about positions −10 and +10 from the start site, may also be employed to inhibit gene expression. Similarly, inhibition can be achieved using triple helix base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors, or regulatory molecules. Recent therapeutic advances using triplex DNA have been described in the literature. (See, e.g., Gee, J. E. et al. (1994) in Huber, B. E. and B. I. Carr, Molecular and Immunologic Approaches, Futura Publishing, Mt. Kisco N.Y., pp. 163-177.) A complementary sequence or antisense molecule may also be designed to block translation of mRNA by preventing the transcript from binding to ribosomes.

[0255] Ribozymes, enzymatic RNA molecules, may also be used to catalyze the specific cleavage of RNA. The mechanism of ribozyme action involves sequence-specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage. For example, engineered hammerhead motif ribozyme molecules may specifically and efficiently catalyze endonucleolytic cleavage of sequences encoding KAP.

[0256] Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, including the following sequences: GUA, GUU, and GUC. Once identified, short RNA sequences of between 15 and 20 ribonucleotides, corresponding to the region of the target gene containing the cleavage site, may be evaluated for secondary structural features which may render the oligonucleotide inoperable. The suitability of candidate targets may also be evaluated by testing accessibility to hybridization with complementary oligonucleotides using ribonuclease protection assays.

[0257] Complementary ribonucleic acid molecules and ribozymes of the invention may be prepared by any method known in the art for the synthesis of nucleic acid molecules. These include techniques for chemically synthesizing oligonucleotides such as solid phase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA sequences encoding KAP. Such DNA sequences may be incorporated into a wide variety of vectors with suitable RNA polymerase promoters such as T7 or SP6. Alternatively, these cDNA constructs that synthesize complementary RNA, constitutively or inducibly, can be introduced into cell lines, cells, or tissues.

[0258] RNA molecules may be modified to increase intracellular stability and half-life. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5′ and/or 3′ ends of the molecule, or the use of phosphorothioate or 2′ O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. This concept is inherent in the production of PNAs and can be extended in all of these molecules by the inclusion of nontraditional bases such as inosine, queosine, and wybutosine, as well as acetyl-, methyl-, thio-, and similarly modified forms of adenine, cytidine, guanine, thymine, and uridine which are not as easily recognized by endogenous endonucleases.

[0259] An additional embodiment of the invention encompasses a method for screening for a compound which is effective in altering expression of a polynucleotide encoding KAP. Compounds which may be effective in altering expression of a specific polynucleotide may include, but are not limited to, oligonucleotides, antisense oligonucleotides, triple helix-forming oligonucleotides, transcription factors and other polypeptide transcriptional regulators, and non-macromolecular chemical entities which are capable of interacting with specific polynucleotide sequences. Effective compounds may alter polynucleotide expression by acting as either inhibitors or promoters of polynucleotide expression. Thus, in the treatment of disorders associated with increased KAP expression or activity, a compound which specifically inhibits expression of the polynucleotide encoding KAP may be therapeutically useful, and in the treatment of disorders associated with decreased KAP expression or activity, a compound which specifically promotes expression of the polynucleotide encoding KAP may be therapeutically useful.

[0260] At least one, and up to a plurality, of test compounds may be screened for effectiveness in altering expression of a specific polynucleotide. A test compound may be obtained by any method commonly known in the art, including chemical modification of a compound known to be effective in altering polynucleotide expression; selection from an existing, commercially-available or proprietary library of naturally-occurring or non-natural chemical compounds; rational design of a compound based on chemical and/or structural properties of the target polynucleotide; and selection from a library of chemical compounds created combinatorially or randomly. A sample comprising a polynucleotide encoding KAP is exposed to at least one test compound thus obtained. The sample may comprise, for example, an intact or permeabilized cell, or an in vitro cell-free or reconstituted biochemical system. Alterations in the expression of a polynucleotide encoding KAP are assayed by any method commonly known in the art. Typically, the expression of a specific nucleotide is detected by hybridization with a probe having a nucleotide sequence complementary to the sequence of the polynucleotide encoding KAP. The amount of hybridization may be quantified, thus forming the basis for a comparison of the expression of the polynucleotide both with and without exposure to one or more test compounds. Detection of a change in the expression of a polynucleotide exposed to a test compound indicates that the test compound is effective in altering the expression of the polynucleotide. A screen for a compound effective in altering expression of a specific polynucleotide can be carried out, for example, using a Schizosaccharomyces pombe gene expression system (Atkins, D. et al. (1999) U.S. Pat. No. 5,932,435; Arndt, G. M. et al. (2000) Nucleic Acids Res. 28:E15) or a human cell line such as HeLa cell (Clarke, M. L. et al. (2000) Biochem. Biophys. Res. Commun. 268:8-13). A particular embodiment of the present invention involves screening a combinatorial library of oligonucleotides (such as deoxyribonucleotides, ribonucleotides, peptide nucleic acids, and modified oligonucleotides) for antisense activity against a specific polynucleotide sequence (Bruice, T. W. et al. (1997) U.S. Pat. No. 5,686,242; Bruice, T. W. et al. (2000) U.S. Pat. No. 6,022,691).

[0261] Many methods for introducing vectors into cells or tissues are available and equally suitable for use in vivo, in vitro, and ex vivo. For ex vivo therapy, vectors may be introduced into stem cells taken from the patient and clonally propagated for autologous transplant back into that same patient. Delivery by transfection, by liposome injections, or by polycationic amino polymers may be achieved using methods which are well known in the art. (See, e.g., Goldman, C. K. et al. (1997) Nat. Biotechnol. 15:462-466.)

[0262] Any of the therapeutic methods described above may be applied to any subject in need of such therapy, including, for example, mammals such as humans, dogs, cats, cows, horses, rabbits, and monkeys.

[0263] An additional embodiment of the invention relates to the administration of a composition which generally comprises an active ingredient formulated with a pharmaceutically acceptable excipient. Excipients may include, for example, sugars, starches, celluloses, gums, and proteins. Various formulations are commonly known and are thoroughly discussed in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing, Easton Pa.). Such compositions may consist of KAP, antibodies to KAP, and mimetics, agonists, antagonists, or inhibitors of KAP.

[0264] The compositions utilized in this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal means.

[0265] Compositions for pulmonary administration may be prepared in liquid or dry powder form. These compositions are generally aerosolized immediately prior to inhalation by the patient. In the case of small molecules (e.g. traditional low molecular weight organic drugs), aerosol delivery of fast-acting formulations is well-known in the art. In the case of macromolecules (e.g. larger peptides and proteins), recent developments in the field of pulmonary delivery via the alveolar region of the lung have enabled the practical delivery of drugs such as insulin to blood circulation (see, e.g., Patton, J. S. et al., U.S. Pat. No. 5,997,848). Pulmonary delivery has the advantage of administration without needle injection, and obviates the need for potentially toxic penetration enhancers.

[0266] Compositions suitable for use in the invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.

[0267] Specialized forms of compositions may be prepared for direct intracellular delivery of macromolecules comprising KAP or fragments thereof. For example, liposome preparations containing a cell-impermeable macromolecule may promote cell fusion and intracellular delivery of the macromolecule. Alternatively, KAP or a fragment thereof may be joined to a short cationic N-terminal portion from the HIV Tat-1 protein. Fusion proteins thus generated have been found to transduce into the cells of all tissues, including the brain, in a mouse model system (Schwarze, S. R. et al. (1999) Science 285:1569-1572).

[0268] For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models such as mice, rats, rabbits, dogs, monkeys, or pigs. An animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.

[0269] A therapeutically effective dose refers to that amount of active ingredient, for example KAP or fragments thereof, antibodies of KAP, and agonists, antagonists or inhibitors of KAP, which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or with experimental animals, such as by calculating the ED₅₀ (the dose therapeutically effective in 50% of the population) or LD₅₀ (the dose lethal to 50% of the population) statistics. The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the LD₅₀/ED₅₀ ratio. Compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies are used to formulate a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that includes the ED₅₀ with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, the sensitivity of the patient, and the route of administration.

[0270] The exact dosage will be determined by the practitioner, in light of factors related to the subject requiring treatment. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, the general health of the subject, the age, weight, and gender of the subject, time and frequency of administration, drug combination(s), reaction sensitivities, and response to therapy. Long-acting compositions may be administered every 3 to 4 days, every week, or biweekly depending on the half-life and clearance rate of the particular formulation.

[0271] Normal dosage amounts may vary from about 0.1 μg to 100,000 μg, up to a total dose of about 1 gram, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art. Those skilled in the art will employ different formulations for nucleotides than for proteins or their inhibitors. Similarly, delivery of polynucleotides or polypeptides will be specific to particular cells, conditions, locations, etc.

Diagnostics

[0272] In another embodiment, antibodies which specifically bind KAP may be used for the diagnosis of disorders characterized by expression of KAP, or in assays to monitor patients being treated with KAP or agonists, antagonists, or inhibitors of KAP. Antibodies useful for diagnostic purposes may be prepared in the same manner as described above for therapeutics. Diagnostic assays for KAP include methods which utilize the antibody and a label to detect KAP in human body fluids or in extracts of cells or tissues. The antibodies may be used with or without modification, and may be labeled by covalent or non-covalent attachment of a reporter molecule. A wide variety of reporter molecules; several of which are described above, are known in the art and may be used.

[0273] A variety of protocols for measuring KAP, including ELISAs, RIAs, and FACS, are known in the art and provide a basis for diagnosing altered or abnormal levels of KAP expression. Normal or standard values for KAP expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, for example, human subjects, with antibodies to KAP under conditions suitable for complex formation. The amount of standard complex formation may be quantitated by various methods, such as photometric means. Quantities of KAP expressed in subject, control, and disease samples from biopsied tissues are compared with the standard values. Deviation between standard and subject values establishes the parameters for diagnosing disease.

[0274] In another embodiment of the invention, the polynucleotides encoding KAP may be used for diagnostic purposes. The polynucleotides which may be used include oligonucleotide sequences, complementary RNA and DNA molecules, and PNAs. The polynucleotides may be used to detect and quantify gene expression in biopsied tissues in which expression of KAP may be correlated with disease. The diagnostic assay may be used to determine absence, presence, and excess expression of KAP, and to monitor regulation of KAP levels during therapeutic intervention.

[0275] In one aspect, hybridization with PCR probes which are capable of detecting polynucleotide sequences, including genomic sequences, encoding KAP or closely related molecules may be used to identify nucleic acid sequences which encode KAP. The specificity of the probe, whether it is made from a highly specific region, e.g., the 5′regulatory region, or from a less specific region, e.g., a conserved motif, and the stringency of the hybridization or amplification will determine whether the probe identifies only naturally occurring sequences encoding KAP, allelic variants, or related sequences.

[0276] Probes may also be used for the detection of related sequences, and may have at least 50% sequence identity to any of the KAP encoding sequences. The hybridization probes of the subject invention may be DNA or RNA and may be derived from the sequence of SEQ ID NO:21-40 or from genomic sequences including promoters, enhancers, and introns of the KAP gene.

[0277] Means for producing specific hybridization probes for DNAs encoding KAP include the cloning of polynucleotide sequences encoding KAP or KAP derivatives into vectors for the production of mRNA probes. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by means of the addition of the appropriate RNA polymerases and the appropriate labeled nucleotides. Hybridization probes may be labeled by a variety of reporter groups, for example, by radionuclides such as ³P or ³⁵S, or-by enzymatic labels, such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems, and the like.

[0278] Polynucleotide sequences encoding KAP may be used for the diagnosis of disorders associated with expression of KAP. Examples of such disorders include, but are not limited to, a cardiovascular disorder such as arteriovenous fistula, atherosclerosis, hypertension, vasculitis, Raynaud's disease, aneurysms, arterial dissections, varicose veins, thrombophlebitis and phlebothrombosis, vascular tumors, and complications of thrombolysis, balloon angioplasty, vascular replacement, and coronary artery bypass graft surgery, congestive heart failure, ischemic heart disease, angina pectoris, myocardial infarction, hypertensive heart disease, degenerative valvular heart disease, calcific aortic valve stenosis, congenitally bicuspid aortic valve, mitral annular calcification, mitral valve prolapse, rheumatic fever and rheumatic heart disease, infective endocarditis, nonbacterial thrombotic endocarditis, endocarditis of systemic lupus erythematosus, carcinoid heart disease, cardiomyopathy, myocarditis, pericarditis, neoplastic heart disease, congenital heart disease, and complications of cardiac transplantation, congenital lung anomalies, atelectasis, pulmonary congestion and edema, pulmonary embolism, pulmonary hemorrhage, pulmonary infarction, pulmonary hypertension, vascular sclerosis, obstructive pulmonary disease, restrictive pulmonary disease, chronic obstructive pulmonary disease, emphysema, chronic bronchitis, bronchial asthma, bronchiectasis, bacterial pneumonia, viral and mycoplasmal pneumonia, lung abscess, pulmonary tuberculosis, diffuse interstitial diseases, pneumoconioses, sarcoidosis, idiopathic pulmonary fibrosis, desquamative interstitial pneumonitis, hypersensitivity pneumonitis, pulmonary eosinophilia bronchiolitis obliterans-organizing pneumonia, diffuse pulmonary hemorrhage syndromes, Goodpasture's syndromes, idiopathic pulmonary hemosiderosis, pulmonary involvement in collagen-vascular disorders, pulmonary alveolar proteinosis, lung tumors, inflammatory and noninflammatory pleural effusions, pneumothorax, pleural tumors, drug-induced lung disease, radiation-induced lung disease, and complications of lung transplantation; an immune disorder such as acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes meritus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infections, and trauma; a neurological disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease, prion diseases including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorders of the central nervous system including Down syndrome, cerebral palsy, neuroskeletal disorders, autonomic nervous system disorders, cranial nerve disorders, spinal cord diseases, muscular dystrophy and other neuromuscular disorders, peripheral nervous system disorders, dermatomyositis and polymyositis, inherited, metabolic, endocrine, and toxic myopathies, myasthenia gravis, periodic paralysis, mental disorders including mood, anxiety, and schizophrenic disorders, seasonal affective disorder (SAD), akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, Tourette's disorder, progressive supranuclear palsy, corticobasal degeneration, and familial frontotemporal dementia; a growth and developmental disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, renal tubular acidosis, anemia, Cushing's syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy, epilepsy, gonadal dysgenesis, WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas, hereditary neuropathies such as Charcot-Marie-Tooth disease and neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders such as Syndenham's chorea and cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital glaucoma, cataract, and sensorineural hearing loss; a lipid disorder such as fatty liver, cholestasis, primary. bilary cirrhosis, carnitine deficiency, carnitine palmitoyltransferase deficiency, myoadenylate deaminase deficiency, hypertriglyceridemia, lipid storage disorders such Fabry's disease, Gaucher's disease, Niemann-Pick's disease, metachromatic leukodystrophy, adrenoleukodystrophy, GM₂ gangliosidosis, and ceroid lipofuscinosis, abetalipoproteinemia, Tangier disease, hyperlipoproteinemia, diabetes mellitus, lipodystrophy, lipomatoses, acute panniculitis, disseminated fat necrosis, adiposis dolorosa, lipoid adrenal hyperplasia, minimal change disease, lipomas, atherosclerosis, hypercholesterolemia, hypercholesterolemia with hypertriglyceridemia, primary hypoalphalipoproteinemia, hypothyroidism, renal disease, liver disease, lecithin:cholesterol acyltransferase deficiency, cerebrotendinous xanthomatosis, sitosterolemia, hypocholesterolemia, Tay-Sachs disease, Sandhoff's disease, hyperlipidemia, hyperlipemia, lipid myopathies, and obesity; and a cell proliferative disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, uterus, leukemias such as multiple myeloma, and lymphomas such as Hodgkin's disease. The polynucleotide sequences encoding KAP may be used in Southern or northern analysis, dot blot, or other membrane-based technologies; in PCR technologies; in dipstick, pin, and multiformat ELISA-like assays; and in microarrays utilizing fluids or tissues from patients to detect altered KAP expression. Such qualitative or quantitative methods are well known in the art.

[0279] In a particular aspect, the nucleotide sequences encoding KAP may be useful in assays that detect the presence of associated disorders, particularly those mentioned above. The nucleotide sequences encoding KAP may be labeled by standard methods and added to a fluid or tissue sample from a patient under conditions suitable for the formation of hybridization complexes. After a suitable incubation period, the sample is washed and the signal is quantified and compared with a standard value. If the amount of signal in the patient sample is significantly altered in comparison to a control sample then the presence of altered levels of nucleotide sequences encoding KAP in the sample indicates the presence of the associated disorder. Such assays may also be used to evaluate the efficacy of a particular therapeutic treatment regimen in animal studies, in clinical trials, or to monitor the treatment of an individual patient.

[0280] In order to provide a basis for the diagnosis of a disorder associated with expression of KAP, a normal or standard profile for expression is established. This may be accomplished by combining body fluids or cell extracts taken from normal subjects, either animal or human, with a sequence, or a fragment thereof, encoding KAP, under conditions suitable for hybridization or amplification. Standard hybridization may be quantified by comparing the values obtained from normal subjects with values from an experiment in which a known amount of a substantially purified polynucleotide is used. Standard values obtained in this manner may be compared with values obtained from samples from patients who are symptomatic for a disorder. Deviation from standard values is used to establish the presence of a disorder.

[0281] Once the presence of a disorder is established and a treatment protocol is initiated, hybridization assays may be repeated on a regular basis to determine if the level of expression in the patient begins to approximate that which is observed in the normal subject. The results obtained from successive assays may be used to show the efficacy of treatment over a period ranging from several days to months.

[0282] With respect to cancer, the presence of an abnormal amount of transcript (either under- or overexpressed) in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.

[0283] Additional diagnostic uses for oligonucleotides designed from the sequences encoding KAP may involve the use of PCR. These oligomers may be chemically synthesized, generated enzymatically, or produced in vitro. Oligomers will preferably contain a fragment of a polynucleotide encoding KAP, or a fragment of a polynucleotide complementary to the polynucleotide encoding KAP, and will be employed under optimized conditions for identification of a specific gene or condition. Oligomers may also be employed under less stringent conditions for detection or quantification of closely related DNA or RNA sequences.

[0284] In a particular aspect, oligonucleotide primers derived from the polynucleotide sequences encoding KAP may be used to detect single nucleotide polymorphisms (SNPs). SNPs are substitutions, insertions and deletions that are a frequent cause of inherited or acquired genetic disease in humans. Methods of SNP detection include, but are not limited to, single-stranded conformation polymorphism (SSCP) and fluorescent SSCP (fSSCP) methods. In SSCP, oligonucleotide primers derived from the polynucleotide sequences encoding KAP are used to amplify DNA using the polymerase chain reaction (PCR). The DNA may be derived, for example, from diseased or normal tissue, biopsy samples, bodily fluids, and the like. SNPs in the DNA cause differences in the secondary and tertiary structures of PCR products in single-stranded form, and these differences are detectable using gel electrophoresis in non-denaturing gels. In fSCCP, the oligonucleotide primers are fluorescently labeled, which allows detection of the amplimers in high-throughput equipment such as DNA sequencing machines. Additionally, sequence database analysis methods, termed in silico SNP (isSNP), are capable of identifying polymorphisms by comparing the sequence of individual overlapping DNA fragments which assemble into a common consensus sequence. These computer-based methods filter out sequence variations due to laboratory preparation of DNA and sequencing errors using statistical models and automated analyses of DNA sequence chromatograms. In the alternative, SNPs may be detected and characterized by mass spectrometry using, for example, the high throughput MASSARRAY system (Sequenom, Inc., San Diego Calif.).

[0285] Methods which may also be used to quantify the expression of KAP include radiolabeling or biotinylating nucleotides, coamplification of a control nucleic acid, and interpolating results from standard curves. (See, e.g., Melby, P. C. et al. (1993) J. Immunol. Methods 159:235-244; Duplaa, C. et al. (1993) Anal. Biochem. 212:229-236.) The speed of quantitation of multiple samples may be accelerated by running the assay in a high-throughput format where the oligomer or polynucleotide of interest is presented in various dilutions and a spectrophotometric or colorimetric response gives rapid quantitation.

[0286] In further embodiments, oligonucleotides or longer fragments derived from any of the polynucleotide sequences described herein may be used as elements on a microarray. The microarray can be used in transcript imaging techniques which monitor the relative expression levels of large numbers of genes simultaneously as described below. The microarray may also be used to identify genetic variants, mutations, and polymorphisms. This information may be used to determine gene function, to understand the genetic basis of a disorder, to diagnose a disorder, to monitor progression/regression of disease as a function of gene expression, and to develop and monitor the activities of therapeutic agents in the treatment of disease. In particular, this information may be used to develop a pharmacogenomic profile of a patient in order to select the most appropriate and effective treatment regimen for that patient. For example, therapeutic agents which are highly effective and display the fewest side effects may be selected for a patient based on his/her pharmacogenomic profile.

[0287] In another embodiment, KAP, fragments of KAP, or antibodies specific for KAP may be used as elements on a microarray. The microarray may be used to monitor or measure protein-protein interactions, drug-target interactions, and gene expression profiles, as described above.

[0288] A particular embodiment relates to the use of the polynucleotides of the present invention to generate a transcript image of a tissue or cell type. A transcript image represents the global pattern of gene expression by a particular tissue or cell type. Global gene expression patterns are analyzed by quantifying the number of expressed genes and their relative abundance under given conditions and at a given time. (See Seilhamer et al., “Comparative Gene Transcript Analysis,” U.S. Pat. No. 5,840,484, expressly incorporated by reference herein.) Thus a transcript image may be generated by hybridizing the polynucleotides of the present invention or their complements to the totality of transcripts or reverse transcripts of a particular tissue or cell type. In one embodiment, the hybridization takes place in high-throughput format, wherein the polynucleotides of the present invention or their complements comprise a subset of a plurality of elements on a microarray. The resultant transcript image would provide a profile of gene activity.

[0289] Transcript images may be generated using transcripts isolated from tissues, cell lines, biopsies, or other biological samples. The transcript image may thus reflect gene expression in vivo, as in the case of a tissue or biopsy sample, or in vitro, as in the case of a cell line.

[0290] Transcript images which profile the expression of the polynucleotides of the present invention may also be used in conjunction with in vitro model systems and preclinical evaluation of pharmaceuticals, as well as toxicological testing of industrial and naturally-occurring environmental compounds. All compounds induce characteristic gene expression patterns, frequently termed molecular fingerprints or toxicant signatures, which are indicative of mechanisms of action and toxicity (Nuwaysir, E. F. et al. (1999) Mol. Carcinog. 24:153-159; Steiner, S. and N. L. Anderson (2000) Toxicol. Lett. 112-113:467471, expressly incorporated by reference herein). If a test compound has a signature similar to that of a compound with known toxicity, it is likely to share those toxic properties. These fingerprints or signatures are most useful and refined when they contain expression information from a large number of genes and gene families. Ideally, a genome-wide measurement of expression provides the highest quality signature. Even genes whose expression is not altered by any tested compounds are important as well, as the levels of expression of these genes are used to normalize the rest of the expression data. The normalization procedure is useful for comparison of expression data after treatment with different compounds. While the assignment of gene function to elements of a toxicant signature aids in interpretation of toxicity mechanisms, knowledge of gene function is not necessary for the statistical matching of signatures which leads to prediction of toxicity. (See, for example, Press Release 00-02 from the National Institute of Environmental Health Sciences, released Feb. 29, 2000, available at http://www.niehs.nih.gov/oc/news/toxchip.htm.) Therefore, it is important and desirable in toxicological screening using toxicant signatures to include all expressed gene sequences.

[0291] In one embodiment, the toxicity of a test compound is assessed by treating a biological sample containing nucleic acids with the test compound. Nucleic acids that are expressed in the treated biological sample are hybridized with one or more probes specific to the polynucleotides of the present invention, so that transcript levels corresponding to the polynucleotides of the present invention may be quantified. The transcript levels in the treated biological sample are compared with levels in an untreated biological sample. Differences in the transcript levels between the two samples are indicative of a toxic response caused by the test compound in the treated sample.

[0292] Another particular embodiment relates to the use of the polypeptide sequences of the present invention to analyze the proteome of a tissue or cell type. The term proteome refers to the global pattern of protein expression in a particular tissue or cell type. Each protein component of a proteome can be subjected individually to further analysis. Proteome expression patterns, or profiles, are analyzed by quantifying the number of expressed proteins and their relative abundance under given conditions and at a given time. A profile of a cell's proteome may thus be generated by separating and analyzing the polypeptides of a particular tissue or cell type. In one embodiment, the separation is achieved using two-dimensional gel electrophoresis, in which proteins from a sample are separated by isoelectric focusing in the first dimension, and then according to molecular weight by sodium dodecyl sulfate slab gel electrophoresis in the second dimension (Steiner and Anderson, supra). The proteins are visualized in the gel as discrete and uniquely positioned spots, typically by staining the gel with an agent such as Coomassie Blue or silver or fluorescent stains. The optical density of each protein spot is generally proportional to the level of the protein in the sample. The optical densities of equivalently positioned protein spots from different samples, for example, from biological samples either treated or untreated with a test compound or therapeutic agent, are compared to identify any changes in protein spot density related to the treatment. The proteins in the spots are partially sequenced using, for example, standard methods employing chemical or enzymatic cleavage followed by mass spectrometry. The identity of the protein in a spot may be determined by comparing its partial sequence, preferably of at least 5 contiguous amino acid residues, to the polypeptide sequences of the present invention. In some cases, further sequence data may be obtained for definitive protein identification.

[0293] A proteomic profile may also be generated using antibodies specific for KAP to quantify the levels of KAP expression. In one embodiment, the antibodies are used as elements on a microarray, and protein expression levels are quantified by exposing the microarray to the sample and detecting the levels of protein bound to each array element (Lueking, A. et al. (1999) Axial. Biochem. 270:103-111; Mendoze, L. G. et al. (1999) Biotechniques 27:778-788). Detection may be performed by a variety of methods known in the art, for example, by reacting the proteins in the sample with a thiol- or amino-reactive fluorescent compound and detecting the amount of fluorescence bound at each array element.

[0294] Toxicant signatures at the proteome level are also useful for toxicological screening, and should be analyzed in parallel with toxicant signatures at the transcript level. There is a poor correlation between transcript and protein abundances for some proteins in some tissues (Anderson, N. L. and J. Seilhamer (1997) Electrophoresis 18:533-537), so proteome toxicant signatures may be useful in the analysis of compounds which do not significantly affect the transcript image, but which alter the proteomic profile. In addition, the analysis of transcripts in body fluids is difficult, due to rapid degradation of mRNA, so proteomic profiling may be more reliable and informative in such cases.

[0295] In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins that are expressed in the treated biological sample are separated so that the amount of each protein can be quantified. The amount of each protein is compared to the amount of the corresponding protein in an untreated biological sample. A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample. Individual proteins are identified by sequencing the amino acid residues of the individual proteins and comparing these partial sequences to the polypeptides of the present invention.

[0296] In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins from the biological sample are incubated with antibodies specific to the polypeptides of the present invention. The amount of protein recognized by the antibodies is quantified. The amount of protein in the treated biological sample is compared with the amount in an untreated biological sample. A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample.

[0297] Microarrays may be prepared, used, and analyzed using methods known in the art. (See, e.g., Brennan, T. M. et al. (1995) U.S. Pat. No. 5,474,796; Schena, M. et al. (1996) Proc. Natl. Acad. Sci. USA 93:10614-10619; Baldeschweiler et al. (1995) PCT application WO95/251116; Shalon, D. et al. (1995) PCT application WO95/35505; Heller, R. A. et al. (1997) Proc. Natl. Acad. Sci. USA 94:2150-2155; and Heller, M. J. et al. (1997) U.S. Pat. No. 5,605,662.) Various types of microarrays are well known and thoroughly described in DNA Microarrays: A Practical Approach, M. Schena, ed. (1999) Oxford University Press, London, hereby expressly incorporated by reference.

[0298] In another embodiment of the invention, nucleic acid sequences encoding KAP may be used to generate hybridization probes useful in mapping the naturally occurring genomic sequence. Either coding or noncoding sequences may be used, and in some instances, noncoding sequences may be preferable over coding sequences. For example, conservation of a coding sequence among members of a multi-gene family may potentially cause undesired cross hybridization during chromosomal mapping. The sequences may be mapped to a particular chromosome, to a specific region of a chromosome, or to artificial chromosome constructions, e.g., human artificial chromosomes (HACs), yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), bacterial P1 constructions, or single chromosome cDNA libraries. (See, e.g., Harrington, J. J. et al. (1997) Nat. Genet. 15:345-355; Price, C. M. (1993) Blood Rev. 7:127-134; and Trask, B. J. (1991) Trends Genet. 7:149-154.) Once mapped, the nucleic acid sequences of the invention may be used to develop genetic linkage maps, for example, which correlate the inheritance of a disease state with the inheritance of a particular chromosome region or restriction fragment length polymorphism (RFLP). (See, for example, Lander, E. S. and D. Botstein (1986) Proc. Natl. Acad. Sci. USA 83:7353-7357.)

[0299] Fluorescent in situ hybridization (FISH) may be correlated with other physical and genetic map data. (See, e.g., Heinz-Ulrich, et al. (1995) in Meyers, supra, pp. 965-968.) Examples of genetic map data can be found in various scientific journals or at the Online Mendelian Inheritance in Man (OMIM) World Wide Web site. Correlation between the location of the gene encoding KAP on a physical map and a specific disorder, or a predisposition to a specific disorder, may help define the region of DNA associated with that disorder and thus may further positional cloning efforts.

[0300] In situ hybridization of chromosomal preparations and physical mapping techniques, such as linkage analysis using established chromosomal markers, may be used for extending genetic maps. Often the placement of a gene on the chromosome of another mammalian species, such as mouse, may reveal associated markers even if the exact chromosomal locus is not known. This information is valuable to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once the gene or genes responsible for a disease or syndrome have been crudely localized by genetic linkage to a particular genomic region, e.g., ataxia-telangiectasia to 11q22-23, any sequences mapping to that area may represent associated or regulatory genes for further investigation. (See, e.g., Gatti, R. A. et al. (1988) Nature 336:577-580.) The nucleotide sequence of the instant invention may also be used to detect differences in the chromosomal location due to translocation, inversion, etc., among normal, carrier, or affected individuals.

[0301] In another embodiment of the invention, KAP, its catalytic or immunogenic fragments, or oligopeptides thereof can be used for screening libraries of compounds in any of a variety of drug screening techniques. The fragment employed in such screening may be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. The formation of binding complexes between KAP and the agent being tested may be measured.

[0302] Another technique for drug screening provides for high throughput screening of compounds having suitable binding affinity to the protein of interest. (See, e.g., Geysen, et al. (1984) PCT application WO84/03564.) In this method, large numbers of different small test compounds are synthesized on a solid substrate. The test compounds are reacted with KAP, or fragments thereof, and washed. Bound KAP is then detected by methods well known in the art. Purified KAP can also be coated directly onto plates for use in the aforementioned drug screening techniques. Alternatively, non-neutralizing antibodies can be used to capture the peptide and immobilize it on a solid support.

[0303] In another embodiment, one may use competitive drug screening assays in which neutralizing antibodies capable of binding KAP specifically compete with a test compound for binding KAP. In this manner, antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with KAP.

[0304] In additional embodiments, the nucleotide sequences which encode KAP may be used in any molecular biology techniques that have yet to be developed, provided the new techniques rely on properties of nucleotide sequences that are currently known, including, but not limited to, such properties as the triplet genetic code and specific base pair interactions.

[0305] Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

[0306] The disclosures of all patents, applications and publications, mentioned above and below, including U.S. Ser. No. 60/254,034, U.S. Ser. No. 60/255,756, U.S. Ser. No. 60/251,814, U.S. Ser. No. 60/256,172, U.S. Ser. No. 60/257,416, U.S. Ser. No. 60/260,912, U.S. Ser. No. 60/264,344, and U.S. Ser. No.60/266,017, are expressly incorporated by reference herein.

EXAMPLES 1. Construction of cDNA Libraries

[0307] Incyte cDNAs were derived from cDNA libraries described in the LIFESEQ GOLD database (Incyte Genomics, Palo Alto Calif.). Some tissues were homogenized and lysed in guanidinium isothiocyanate, while others were homogenized and lysed in phenol or in a suitable mixture of denaturants, such as TRIZOL (Life Technologies), a monophasic solution of phenol and guanidine isothiocyanate. The resulting lysates were centrifuged over CsCl cushions or extracted with chloroform. RNA was precipitated from the lysates with either isopropanol or sodium acetate and ethanol, or by other routine methods.

[0308] Phenol extraction and precipitation of RNA were repeated as necessary to increase RNA purity. In some cases, RNA was treated with DNase. For most libraries, poly(A)+RNA was isolated using oligo d(T)-coupled paramagnetic particles (Promega), OLIGOTEX latex particles (QIAGEN, Chatsworth Calif.), or an OLIGOTEX mRNA purification kit (QIAGEN). Alternatively, RNA was isolated directly from tissue lysates using other RNA isolation kits, e.g., the POLY(A)PURE mRNA purification kit (Ambion, Austin Tex.).

[0309] In some cases, Stratagene was provided with RNA and constructed the corresponding cDNA libraries. Otherwise, cDNA was synthesized and cDNA libraries were constructed with the UNIZAP vector system (Stratagene) or SUPERSCRIPT plasmid system (Life Technologies), using the recommended procedures or similar methods known in the art. (See, e.g., Ausubel, 1997, supra, units 5.1-6.6.) Reverse transcription was initiated using oligo d(T) or random primers. Synthetic oligonucleotide adapters were ligated to double stranded cDNA, and the cDNA was digested with the appropriate restriction enzyme or enzymes. For most libraries, the cDNA was size-selected (300-1000 bp) using SEPHACRYL S1000, SEPHAROSE CL2B, or SEPHAROSE CL4B column chromatography (Amersham Pharmacia Biotech) or preparative agarose gel electrophoresis. cDNAs were ligated into compatible restriction enzyme sites of the polylinker of a suitable plasmid, e.g., PBLUESCRIPT plasmid (Stratagene), PSPORT1 plasmid (Life Technologies), PCDNA2.1 plasmid (Invitrogen, Carlsbad Calif.), PBK-CMV plasmid (Stratagene), PCR2-TOPOTA plasmid (Invitrogen), PCMV-ICIS plasmid (Stratagene), pIGEN (Incyte Genomics, Palo Alto Calif.), pRARE (Incyte Genomics), or pINCY (Incyte Genomics), or derivatives thereof. Recombinant plasmids were transformed into competent E. coli cells including XL1-Blue, XL1-BlueMRF, or SOLR from Stratagene or DH5α, DH10B, or ElectroMAX DH10B from Life Technologies.

II. Isolation f cDNA Clones

[0310] Plasmids obtained as described in Example I were recovered from host cells by in vivo excision using the UNIZAP vector system (Stratagene) or by cell lysis. Plasmids were purified using at least one of the following: a Magic or WIZARD Minipreps DNA purification system (Promega); an AGTC Miniprep purification kit (Edge Biosystems, Gaithersburg Md.); and QIAWELL 8 Plasmid, QIAWELL 8 Plus Plasmid, QIAWELL 8 Ultra Plasmid purification systems or the R.E.A.L. PREP 96 plasmid purification kit from QIAGEN. Following precipitation, plasmids were resuspended in 0.1 ml of distilled water and stored, with or without lyophilization, at 4° C.

[0311] Alternatively, plasmid DNA was amplified from host cell lysates using direct link PCR in a high-throughput format (Rao, V. B. (1994) Anal. Biochem. 216:1-14). Host cell lysis and thermal cycling steps were carried out in a single reaction mixture. Samples were processed and stored in 384-well plates, and the concentration of amplified plasmid DNA was quantified fluorometrically using PICOGREEN dye (Molecular Probes, Eugene OR) and a FLUOROSKAN II fluorescence scanner (Labsystems Oy, Helsinki, Finland).

III. Sequencing and Analysis

[0312] Incyte cDNA recovered in plasmids as described in Example II were sequenced as follows. Sequencing reactions were processed using standard methods or high-throughput instrumentation such as the ABI CATALYST 800 (Applied Biosystems) thermal cycler or the PTC-200 thermal cycler (MJ Research) in conjunction with the HYDRA microdispenser (Robbins Scientific) or the MICROLAB 2200 (Hamilton) liquid transfer system. cDNA sequencing reactions were prepared using reagents provided by Amersham Pharmacia Biotech or supplied in ABI sequencing kits such as the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems). Electrophoretic separation of cDNA sequencing reactions and detection of labeled polynucleotides were carried out using the MEGABACE 1000 DNA sequencing system (Molecular Dynamics); the ABI PRISM 373 or 377 sequencing system (Applied Biosystems) in conjunction with standard ABI protocols and base calling software; or other sequence analysis systems known in the art. Reading frames within the cDNA sequences were identified using standard methods (reviewed in Ausubel, 1997, supra, unit 7.7). Some of the cDNA sequences were selected for extension using the techniques disclosed in Example VIII.

[0313] The polynucleotide sequences derived from Incyte cDNAs were validated by removing vector, linker, and poly(A) sequences and by masking ambiguous bases, using algorithms and programs based on BLAST, dynamic programming, and dinucleotide nearest neighbor analysis. The Incyte cDNA sequences or translations thereof were then queried against a selection of public databases such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases, and BLOCKS, PRINTS, DOMO, PRODOM; PROTEOME databases with sequences from Homo sapiens, Rattus norvegicus, Mus musculus, Caenorhabditis elegans, Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Candida albicans (Incyte Genomics, Palo Alto Calif.); and hidden Markov model (HMM)-based protein family databases such as PFAM. (HMM is a probabilistic approach which analyzes consensus primary structures of gene families. See, for example, Eddy, S. R. (1996) Curr. Opin. Struct. Biol. 6:361-365.) The queries were performed using programs based on BLAST, FASTA, BLIMPS, and HMMER. The Incyte cDNA sequences were assembled to produce full length polynucleotide sequences. Alternatively, GenBank cDNAs, GenBank ESTs, stitched sequences, stretched sequences, or Genscan-predicted coding sequences (see Examples IV and V) were used to extend Incyte cDNA assemblages to full length. Assembly was performed using programs based on Phred, Phrap, and Consed, and cDNA assemblages were screened for open reading frames using programs based on GeneMark, BLAST, and PASTA. The full length polynucleotide sequences were translated to derive the corresponding full length polypeptide sequences. Alternatively, a polypeptide of the invention may begin at any of the methionine residues of the full length translated polypeptide. Full length polypeptide sequences were subsequently analyzed by querying against databases such as the GenBank protein databases (genpept), SwissProt, the PROTEOME databases, BLOCKS, PRINTS, DOMO, PRODOM, Prosite, and hidden Markov model (HMM)-based protein family databases such as PFAM. Full length polynucleotide sequences are also analyzed using MACDNASIS PRO software (Hitachi Software Engineering, South San Francisco Calif.) and LASERGENE software (DNASTAR). Polynucleotide and polypeptide sequence alignments are generated using default parameters specified by the CLUSTAL algorithm as incorporated into the MEGALIGN multisequence alignment program (DNASTAR), which also calculates the percent identity between aligned sequences.

[0314] Table 7 summarizes the tools, programs, and algorithms used for the analysis and assembly of Incyte cDNA and full length sequences and provides applicable descriptions, references, and threshold parameters. The first column of Table 7 shows the tools, programs, and algorithms used, the second column provides brief descriptions thereof, the third column presents appropriate references, all of which are incorporated by reference herein in their entirety, and the fourth column presents, where applicable, the scores, probability values, and other parameters used to evaluate the strength of a match between two sequences (the higher the score or the lower the probability value, the greater the identity between two sequences).

[0315] The programs described above for the assembly and analysis of full length polynucleotide and polypeptide sequences were also used to identify polynucleotide sequence fragments from SEQ ID NO:21-40. Fragments from about 20 to about 4000 nucleotides which are useful in hybridization and amplification technologies are described in Table 4, column 2.

IV. Identification and Editing of Coding Sequences from Genomic DNA

[0316] Putative kinases and phosphatases were initially identified by running the Genscan gene identification program against public genomic sequence databases (e.g., gbpri and gbhtg). Genscan is a general-purpose gene identification program which analyzes genomic DNA sequences from a variety of organisms (See Burge, C. and S. Karlin (1997) J. Mol. Biol. 268:78-94, and Burge, C. and S. Karlin (1998) Curr. Opin. Struct. Biol. 8:346-354). The program concatenates predicted exons to form an assembled cDNA sequence extending from a methionine to a stop codon. The output of Genscan is a PASTA database of polynucleotide and polypeptide sequences. The maximum range of sequence for Genscan to analyze at once was set to 30 kb. To determine which of these Genscan predicted cDNA sequences encode kinases and phosphatases, the encoded polypeptides were analyzed by querying against PFAM models for kinases and phosphatases. Potential kinases and phosphatases were also identified by homology to Incyte cDNA sequences that had been annotated as kinases and phosphatases. These selected Genscan-predicted sequences were then compared by BLAST analysis to the genpept and gbpri public databases. Where necessary, the Genscan-predicted sequences were then edited by comparison to the top BLAST hit from genpept to correct errors in the sequence predicted by Genscan, such as extra or omitted exons. BLAST analysis was also used to find any Incyte cDNA or public cDNA coverage of the Genscan-predicted sequences, thus providing evidence for transcription. When Incyte cDNA coverage was available, this information was used to correct or confirm the Genscan predicted sequence. Full length polynucleotide sequences were obtained by assembling Genscan-predicted coding sequences with Incyte cDNA sequences and/or public cDNA sequences using the assembly process described in Example III. Alternatively, full length polynucleotide sequences were derived entirely from edited or unedited Genscan-predicted coding sequences.

V. Assembly of Genomic Sequence Data with cDNA Sequence Data “Stitched” Sequences

[0317] Partial cDNA sequences were extended with exons predicted by the Genscan gene identification program described in Example IV. Partial cDNAs assembled as described in Example III were mapped to genomic DNA and parsed into clusters containing related cDNAs and Genscan exon predictions from one or more genomic sequences. Each cluster was analyzed using an algorithm based on graph theory and dynamic programming to integrate cDNA and genomic information, generating possible splice variants that were subsequently confirmed, edited, or extended to create a full length sequence. Sequence intervals in which the entire length of the interval was present on more than one sequence in the cluster were identified, and intervals thus identified were considered to be equivalent by transitivity. For example, if an interval was present on a cDNA and two genomic sequences, then all three intervals were considered to be equivalent. This process allows unrelated but consecutive genomic sequences to be brought together, bridged by cDNA sequence. Intervals thus identified were then “stitched” together by the stitching algorithm in the order that they appear along their parent sequences to generate the longest possible sequence, as well as sequence variants. Linkages between intervals which proceed along one type of parent sequence (cDNA to cDNA or genomic sequence to genomic sequence) were given preference over linkages which change parent type (cDNA to genomic sequence). The resultant stitched sequences were translated and compared by BLAST analysis to the genpept and gbpri public databases. Incorrect exons predicted by Genscan were corrected by comparison to the top BLAST hit from genpept. Sequences were further extended with additional cDNA sequences, or by inspection of genomic DNA, when necessary.

“Stretched” Sequences

[0318] Partial DNA sequences were extended to full length with an algorithm based on BLAST analysis. First, partial cDNAs assembled as described in Example III were queried against public databases such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases using the BLAST program. The nearest GenBank protein homolog was then compared by BLAST analysis to either Incyte cDNA sequences or GenScan exon predicted sequences described in Example IV. A chimeric protein was generated by using the resultant high-scoring segment pairs (HSPs) to map the translated sequences onto the GenBank protein homolog. Insertions or deletions may occur in the chimeric protein with respect to the original GenBank protein homolog. The GenBank protein homolog, the chimeric protein, or both were used as probes to search for homologous genomic sequences from the public human genome databases. Partial DNA sequences were therefore “stretched” or extended by the addition of homologous genomic sequences. The resultant stretched sequences were examined to determine whether it contained a complete gene.

VI. Chromosomal Mapping of KAP Encoding Polynucleotides

[0319] The sequences which were used to assemble SEQ ID NO:21-40 were compared with sequences from the Incyte LIFESEQ database and public domain databases using BLAST and other implementations of the Smith-Waterman algorithm. Sequences from these databases that matched SEQ ID NO:21-40 were assembled into clusters of contiguous and overlapping sequences using assembly algorithms such as Phrap (Table 7). Radiation hybrid and genetic mapping data available from public resources such as the Stanford Human Genome Center (SHGC), Whitehead Institute for Genome Research (WIGR), and Genethon were used to determine if any of the clustered sequences had been previously mapped. Inclusion of a mapped sequence in a cluster resulted in the assignment of all sequences of that cluster, including its particular SEQ ID NO:, to that map location.

[0320] Map locations are represented by ranges, or intervals, of human chromosomes. The map position of an interval, in centiMorgans, is measured relative to the terminus of the chromosome's p-arm (The centiMorgan (cM) is a unit of measurement based on recombination frequencies between chromosomal markers. On average, 1 cM is roughly equivalent to 1 megabase (Mb) of DNA in humans, although this can vary widely due to hot and cold spots of recombination.) The cM distances are based on genetic markers mapped by Genethon which provide boundaries for radiation hybrid markers whose sequences were included in each of the clusters. Human genome maps and other resources available to the public, such as the NCBI “ceneMap'99” World Wide Web site (http://www.ncbi.nlm nih.gov/genemap/), can be employed to determine if previously identified disease genes map within or in proximity to the intervals indicated above.

[0321] In this manner, SEQ ID NO:33 was mapped to chromosome 12 within the interval from 97.10 to 113.30 centiMorgans. SEQ ID NO:35 was mapped to chromosome 3 within the interval from 16.50 to 30.40 centiMorgans. SEQ ID NO:29 was mapped to chromosome 13 within the interval from 11.60 to 22.80 centiMorgans, to chromosome 15 within the interval from 72.30 to 77.30 centiMorgans, and to chromosome 20 within the interval from 57.70 to 64.10 centiMorgans. More than one map location is reported for SEQ ID NO:29, indicating that sequences having different map locations were assembled into a single cluster. This situation occurs, for example, when sequences having strong similarity, but not complete identity, are assembled into a single cluster.

VII. Analysis of Polynucleotide Expression

[0322] Northern analysis is a laboratory technique used to detect the presence of a transcript of a gene and involves the hybridization of a labeled nucleotide sequence to a membrane on which RNAs from a particular cell type or tissue have been bound. (See, e.g., Sambrook, supra, ch. 7; Ausubel (1995) supra, ch. 4 and 16.)

[0323] Analogous computer techniques applying BLAST were used to search for identical or related molecules in cDNA databases such as GenBank or LIFESEQ (Incyte Genomics). This analysis is much faster than multiple membrane-based hybridizations. In addition, the sensitivity of the computer search can be modified to determine whether any particular match is categorized as exact or similar. The basis of the search is the product score, which is defined as: $\frac{{BLAST}\quad {Score} \times {Percent}\quad {Identity}}{5 \times {minimum}\quad \left\{ {{{length}\quad \left( {{Seq}.\quad 1} \right)},{{length}\left( {{Seq}.\quad 2} \right)}} \right\}}$

[0324] The product score takes into account both the degree of similarity between two sequences and the length of the sequence match. The product score is a normalized value between 0 and 100, and is calculated as follows: the BLAST score is multiplied by the percent nucleotide identity and the product is divided by (5 tires the length of the shorter of the two sequences). The BLAST score is calculated by assigning a score of +5 for every base that matches in a high-scoring segment pair (HSP), and −4 for every mismatch. Two sequences may share more than one HSP (separated by gaps). If there is more than one HSP, then the pair with the highest BLAST score is used to calculate the product score. The product score represents a balance between fractional overlap and quality in a BLAST alignment For example, a product score of 100 is produced only for 100% identity over the entire length of the shorter of the two sequences being compared. A product score of 70 is produced either by 100% identity and 70% overlap at one end, or by 88% identity and 100% overlap at the other. A product score of 50 is produced either by 100% identity and 50% overlap at one end, or 79% identity and 100% overlap.

[0325] Alternatively, polynucleotide sequences encoding KAP are analyzed with respect to the tissue sources from which they were derived. For example, some full length sequences are assembled, at least in part, with overlapping Incyte cDNA sequences (see Example III). Each cDNA sequence is derived from a cDNA library constructed from a human tissue. Each human tissue is classified into one of the following organ/tissue categories: cardiovascular system; connective tissue; digestive system; embryonic structures; endocrine system; exocrine glands; genitalia, female; genitalia, male; germ cells; hemic and immune system; liver; musculoskeletal system; nervous system; pancreas; respiratory system; sense organs; skin; stomatognathic system; unclassified/mixed; or urinary tract. The number of libraries in each category is counted and divided by the total number of libraries across all categories. Similarly, each human tissue is classified into one of the following disease/condition categories: cancer, cell line, developmental, inflammation, neurological, trauma, cardiovascular, pooled, and other, and the number of libraries in each category is counted and divided by the total number of libraries across all categories. The resulting percentages reflect the tissue- and disease-specific expression of cDNA encoding KAP. cDNA sequences and cDNA library/tissue information are found in the LIFESEQ GOLD database (Incyte Genomics, Palo Alto Calif.).

VIII. Extension of KAP Encoding Polynucleotides

[0326] Full length polynucleotide sequences were also produced by extension of an appropriate fragment of the full length molecule using oligonucleotide primers designed from this fragment. One primer was synthesized to initiate 5′ extension of the known fragment, and the other primer was synthesized to initiate 3′extension of the known fragment. The initial primers were designed using OLIGO 4.06 software (National Biosciences), or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the target sequence at temperatures of about 68° C. to about 72° C. Any stretch of nucleotides which would result in hairpin structures and primer-primer dimerizations was avoided.

[0327] Selected human cDNA libraries were used to extend the sequence. If more than one extension was necessary or desired, additional or nested sets of primers were designed.

[0328] High fidelity amplification was obtained by PCR using methods well known in the art. PCR was performed in 96-well plates using the PTC-200 thermal cycler (MJ Research, Inc.). The reaction mix contained DNA template, 200 nmol of each primer, reaction buffer containing Mg²⁺, (NH₄)₂SO₄, and 2-mercaptoethanol, Taq DNA polymerase (Amersham Pharmacia Biotech), ELONGASE enzyme (Life Technologies), and Pfu DNA polymerase (Stratagene), with the following parameters for primer pair PCI A and PCI B: Step 1: 94° C., 3 min; Step 2: 94° C., 15 sec; Step 3: 60° C., 1 min; Step 4: 68° C., 2 min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step 6: 68° C., 5 min; Step 7: storage at 4° C. In the alternative, the parameters for primer pair T7 and SK+ were as follows: Step 1: 94° C., 3 min; Step 2: 94° C., 15 sec; Step 3: 57° C., 1 min; Step 4: 68° C., 2 min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step 6: 68° C., 5 min; Step 7: storage at 4° C.

[0329] The concentration of DNA in each well was determined by dispensing 100 μl PICOGREEN quantitation reagent (0.25% (v/v) PICOGREEN; Molecular Probes, Eugene Oreg.) dissolved in 1×TE and 0.5 μl of undiluted PCR product into each well of an opaque fluorimeter plate (Corning Costar, Acton Mass.), allowing the DNA to bind to the reagent. The plate was scanned in a Fluoroskan II (Labsystems Oy, Helsinki, Finland) to measure the fluorescence of the sample and to quantify the concentration of DNA. A 5 μl to 10 μl aliquot of the reaction mixture was analyzed by electrophoresis on a 1% agarose gel to determine which reactions were successful in extending the sequence.

[0330] The extended nucleotides were desalted and concentrated, transferred to 384-well plates, digested with CviJI cholera virus endonuclease (Molecular Biology Research, Madison Wis.), and sonicated or sheared prior to religation into pUC 18 vector (Amersham Pharmacia Biotech). For shotgun sequencing, the digested nucleotides were separated on low concentration (0.6 to 0.8%) agarose gels, fragments were excised, and agar digested with Agar ACE (Promega). Extended clones were religated using T4 ligase (New England Biolabs, Beverly Mass.) into pUC 18 vector (Amersham Pharmacia Biotech), treated with Pfu DNA polymerase (Stratagene) to fill-in restriction site overhangs, and transfected into competent E. coli cells. Transformed cells were selected on antibiotic-containing media, and individual colonies were picked and cultured overnight at 37° C. in 384-well plates in LB/2×carb liquid media.

[0331] The cells were lysed, and DNA was amplified by PCR using Taq DNA polymerase (Amersham Pharmacia Biotech) and Pfu DNA polymerase (Stratagene) with the following parameters: Step 1: 94° C., 3 min; Step 2: 94° C., 15 sec; Step 3: 60° C., 1 min; Step 4: 72° C., 2 min; Step 5: steps 2, 3, and 4 repeated 29 times; Step 6: 72° C., 5 min; Step 7: storage at 4° C. DNA was quantified by PICOGREEN reagent (Molecular Probes) as described above. Samples with low DNA recoveries were reamplified using the same conditions as described above. Samples were diluted with 20% dimnethysulfoxide (1:2, v/v), and sequenced using DYENAMIC energy transfer sequencing primers and the DYENAMIC DIRECT kit (Amersham Pharmacia Biotech) or the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems).

[0332] In like manner, full length polynucleotide sequences are verified using the above procedure or are used to obtain 5′regulatory sequences using the above procedure along with oligonucleotides designed for such extension, and an appropriate genomic library.

IX. Labeling and Use of Individual Hybridization Probes

[0333] Hybridization probes derived from SEQ ID NO:21-40 are employed to screen cDNAs, genomic DNAs, or mRNAs. Although the labeling of oligonucleotides, consisting of about 20 base pairs, is specifically described, essentially the same procedure is used with larger nucleotide fragments. Oligonucleotides are designed using state-of-the-art software such as OLIGO 4.06 software (National Biosciences) and labeled by combining 50 pmol of each oligomer, 250 μCi of [γ-³²P] adenosine triphosphate (Amersham Pharmacia Biotech), and T4 polynucleotide kinase (DuPont NEN, Boston Mass.). The labeled oligonucleotides are substantially purified using a SEPHADEX G-25 superfine size exclusion dextran bead column (Amersham Pharmacia Biotech). An aliquot containing 10⁷ counts per minute of the labeled probe is used in a typical membrane-based hybridization analysis of human genomic DNA digested with one of the following endonucleases: Ase I, Bgl II, Eco RI, Pst I, Xba I, or Pvu II (DuPont NEN).

[0334] The DNA from each digest is fractionated on a 0.7% agarose gel and transferred to nylon membranes (Nytran Plus, Schleicher & Schuell, Durham N.H.). Hybridization is carried out for 16 hours at 40° C. To remove nonspecific signals, blots are sequentially washed at room temperature under conditions of up to, for example, 0.1× saline sodium citrate and 0.5% sodium dodecyl sulfate. Hybridization patterns are visualized using autoradiography or an alternative imaging means and compared.

X. Microarrays

[0335] The linkage or synthesis of array elements upon a microarray can be achieved utilizing photolithography, piezoelectric printing (ink-jet printing, See, e.g., Baldeschweiler, supra.), mechanical microspotting technologies, and derivatives thereof. The substrate in each of the aforementioned technologies should be uniform and solid with a non-porous surface (Schena (1999), supra). Suggested substrates include silicon, silica, glass slides, glass chips, and silicon wafers. Alternatively, a procedure analogous to a dot or slot blot may also be used to arrange and link elements to the surface of a substrate using thermal, UV, chemical, or mechanical bonding procedures. A typical array may be produced using available methods and machines well known to those of ordinary skill in the art and may contain any appropriate number of elements. (See, e.g., Schena, M. et al. (1995) Science 270:467-470; Shalon, D. et al. (1996) Genome Res. 6:639-645; Marshall, A. and 3. Hodgson (1998) Nat. Biotechnol. 16:27-31.)

[0336] Full length cDNAs, Expressed Sequence Tags (ESTs), or fragments or oligomers thereof may comprise the elements of the microarray. Fragments or oligomers suitable for hybridization can be selected using software well known in the art such as LASERGENE software (DNASTAR). The array elements are hybridized with polynucleotides in a biological sample. The polynucleotides in the biological sample are conjugated to a fluorescent label or other molecular tag for ease of detection. After hybridization, nonhybridized nucleotides from the biological sample are removed, and a fluorescence scanner is used to detect hybridization at each array element. Alternatively, laser desorbtion and mass spectrometry may be used for detection of hybridization. The degree of complementarity and the relative abundance of each polynucleotide which hybridizes to an element on the microarray may be assessed. In one embodiment, microarray preparation and usage is described in detail below.

Tissue or Cell Sample Preparation

[0337] Total RNA is isolated from tissue samples using the guanidinium thiocyanate method and poly(A)⁺ RNA is purified using the oligo-(dT) cellulose method. Each poly(A)⁺ RNA sample is reverse transcribed using MMLV reverse-transcriptase, 0.05 pg/μl oligo-(dT) primer (21mer), 1× first strand buffer, 0.03 units/μl RNase inhibitor, 500 μM dATP, 500 μM dGTP, 500 μM dTTP, 40 μM dCTP, 40 μM dCTP-Cy3 (BDS) or dCTP-Cy5 (Amersham Pharmacia Biotech). The reverse transcription reaction is performed in a 25 ml volume containing 200 ng poly(A)⁺ RNA with GEMBRIGHT kits (Incyte). Specific control poly(A)⁺ RNAs are synthesized by in vitro transcription from non-coding yeast genomic DNA. After incubation at 37° C. for 2 hr, each reaction sample (one with Cy3 and another with Cy5 labeling) is treated with 2.5 ml of 0.5M sodium hydroxide and incubated for 20 minutes at 85° C. to the stop the reaction and degrade the RNA. Samples are purified using two successive CHROMA SPIN 30 gel filtration spin columns (CLONTECH Laboratories, Inc. (CLONTECH), Palo Alto Calif.) and after combining, both reaction samples are ethanol precipitated using 1 ml of glycogen (1 mg/ml), 60 ml sodium acetate, and 300 ml of 100% ethanol. The sample is then dried to completion using a SpeedVAC (Savant Instruments Inc., Holbrook N.Y.) and resuspended in 14 μl 5×SSC10.2% SDS.

Microarry Preparation

[0338] Sequences of the present invention are used to generate array elements. Each array element is amplified from bacterial cells containing vectors with cloned cDNA inserts. PCR amplification uses primers complementary to the vector sequences flanking the cDNA insert. Array elements are amplified in thirty cycles of PCR from an initial quantity of 1-2 ng to a final quantity greater than 5 μg. Amplified array elements are then purified using SEPHACRYL-400 (Amersham Pharmacia Biotech).

[0339] Purified array elements are immobilized on polymer-coated glass slides. Glass microscope slides (Corning) are cleaned by ultrasound in 0.1% SDS and acetone, with extensive distilled water washes between and after treatments. Glass slides are etched in 4% hydrofluoric acid (VWR Scientific Products Corporation (VWR), West Chester Pa.), washed extensively in distilled water, and coated with 0.05% aminopropyl silane (Sigma) in 95% ethanol. Coated slides are cured in a 110° C. oven.

[0340] Array elements are applied to the coated glass substrate using a procedure described in U.S. Pat. No. 5,807,522, incorporated herein by reference. 1 μl of the array element DNA, at an average concentration of 100 ng/μl, is loaded into the open capillary printing element by a high-speed robotic apparatus. The apparatus then deposits about 5 nl of array element sample per slide.

[0341] Microarrays are UV-crosslinked using a STRATALINKER UV-crosslinker (Stratagene). Microarrays are washed at room temperature once in 0.2% SDS and three times in distilled water. Non-specific binding sites are blocked by incubation of microarrays in 0.2% casein in phosphate buffered saline (PBS) (Tropix, Inc., Bedford Mass.) for 30 minutes at 60° C. followed by washes in 0.2% SDS and distilled water as before.

Hybridization

[0342] Hybridization reactions contain 9 μl of sample mixture consisting of 0.2 μg each of Cy3 and Cy5 labeled cDNA synthesis products in 5×SSC, 0.2% SDS hybridization buffer. The sample mixture is heated to 65° C. for 5 minutes and is aliquoted onto the microarray surface and covered with an 1.8 cm² coverslip. The arrays are transferred to a waterproof chamber having a cavity just slightly larger than a microscope slide. The chamber is kept at 100% humidity internally by the addition of 140 μl of 5×SSC in a corner of the chamber. The chamber containing the arrays is incubated for about 6.5 hours at 60° C. The arrays are washed for 10 min at 45° C. in a first wash buffer (1×SSC, 0.1% SDS), three times for 10 minutes each at 45° C. in a second wash buffer (0.1×SSC), and dried.

Detection

[0343] Reporter-labeled hybridization complexes are detected with a microscope equipped with an Innova 70 mixed gas 10 W laser (Coherent, Inc., Santa Clara Calif.) capable of generating spectral lines at 488 nm for excitation of Cy3 and at 632 nm for excitation of Cy5. The excitation laser light is focused on the array using a 20× microscope objective (Nikon, Inc., Melville N.Y.). The slide containing the array is placed on a computer-controlled X-Y stage on the microscope and raster-scanned past the objective. The 1.8 cm×1.8 cm array used in the present example is scanned with a resolution of 20 micrometers.

[0344] In two separate scans, a mixed gas multiline laser excites the two fluorophores sequentially. Emitted light is split, based on wavelength, into two photomultiplier tube detectors (PMT R1477, Hamamatsu Photonics Systems, Bridgewater N.J.) corresponding to the two fluorophores. Appropriate filters positioned between the array and the photomultiplier tubes are used to filter the signals. The emission maxima of the fluorophores used are 565 nm for Cy3 and 650 nm for Cy5. Each array is typically scanned twice, one scan per fluorophore using the appropriate filters at the laser source, although the apparatus is capable of recording the spectra from both fluorophores simultaneously.

[0345] The sensitivity of the scans is typically calibrated using the signal intensity generated by a cDNA control species added to the sample mixture at a known concentration. A specific location on the array contains a complementary DNA sequence, allowing the intensity of the signal at that location to be correlated with a weight ratio of hybridizing species of 1:100,000. When two samples from different sources (e.g., representing test and control cells), each labeled with a different fluorophore, are hybridized to a single array for the purpose of identifying genes that are differentially expressed, the calibration is done by labeling samples of the calibrating cDNA with the two fluorophores and adding identical amounts of each to the hybridization mixture.

[0346] The output of the photomultiplier tube is digitized using a 12-bit RTI-835H analog-to-digital (A/D) conversion board (Analog Devices, Inc., Norwood Mass.) installed in an IBM-compatible PC computer. The digitized data are displayed as an image where the signal intensity is mapped using a linear 20-color transformation to a pseudocolor scale ranging from blue (low signal) to red (high signal). The data is also analyzed quantitatively. Where two different fluorophores are excited and measured simultaneously, the data are first corrected for optical crosstalk (due to overlapping emission spectra) between the fluorophores using each fluorophore's emission spectrum.

[0347] A grid is superimposed over the fluorescence signal image such that the signal from each spot is centered in each element of the grid. The fluorescence signal within each element is then integrated to obtain a numerical value corresponding to the average intensity of the signal. The software used for signal analysis is the GEMTOOLS gene expression analysis program (Incyte).

XI. Complementary Polynucleotides

[0348] Sequences complementary to the KAP-encoding sequences, or any parts thereof, are used to detect, decrease, or inhibit expression of naturally occurring KAP. Although use of oligonucleotides comprising from about 15 to 30 base pairs is described, essentially the same procedure is used with smaller or with larger sequence fragments. Appropriate oligonucleotides are designed using OLIGO 4.06 software (National Biosciences) and the coding sequence of KAP. To inhibit transcription, a complementary oligonucleotide is designed from the most unique 5′ sequence and used to prevent promoter binding to the coding sequence. To inhibit translation, a complementary oligonucleotide is designed to prevent ribosomal binding to the KAP-encoding transcript.

XII. Expression of KAP

[0349] Expression and purification of KAP is achieved using bacterial or virus-based expression systems. For expression of KAP in bacteria, cDNA is subcloned into an appropriate vector containing an antibiotic resistance gene and an inducible promoter that directs high levels of cDNA transcription. Examples of such promoters include, but are not limited to, the trp-lac (tac) hybrid promoter and the T5 or T7 bacteriophage promoter in conjunction with the lac operator regulatory element. Recombinant vectors are transformed into suitable bacterial hosts, e.g., BL21(DE3). Antibiotic resistant bacteria express KAP upon induction with isopropyl beta-D-thiogalactopyranoside (IPTG). Expression of KAP in eukaryotic cells is achieved by infecting insect or mammalian cell lines with recombinant Autographica californica nuclear polyhedrosis virus (AcMNPV), commonly known as baculovirus. The nonessential polyhedrin gene of baculovirus is replaced with cDNA encoding KAP by either homologous recombination or bacterial-mediated transposition involving transfer plasmid intermediates. Viral infectivity is maintained and the strong polyhedrin promoter drives high levels of cDNA transcription. Recombinant baculovirus is used to infect Spodoptera frugiperda (Sf9) insect cells in most cases, or human hepatocytes, in some cases. Infection of the latter requires additional genetic modifications to baculovirus. (See Engelhard, E. K. et al. (1994) Proc. Natl. Acad. Sci. USA 91:3224-3227; Sandig, V. et al. (1996) Hum Gene Ther. 7:1937-1945.)

[0350] In most expression systems, KAP is synthesized as a fusion protein with, e.g., glutathione Stransferase (GST) or a peptide epitope tag, such as FLAG or 6His, permitting rapid, single-step, affinity-based purification of recombinant fusion protein from crude cell lysates. GST, a 26-kilodalton enzyme from Schistosoma japonicum, enables the purification of fusion proteins on immobilized glutathione under conditions that maintain protein activity and antigenicity (Amersham Pharmacia Biotech). Following purification, the GST moiety can be proteolytically cleaved from KAP at specifically engineered sites. FLAG, an 8-amino acid peptide, enables immunoaffinity purification using commercially available monoclonal and polyclonal anti-FLAG antibodies (Eastman Kodak). 6-His, a stretch of six consecutive histidine residues, enables purification on metal-chelate resins (QIAGEN). Methods for protein expression and purification are discussed in Ausubel (1995, supra, ch. 10 and 16). Purified KAP obtained by these methods can be used directly in the assays shown in Examples XVI, XVII, XVIII, XIX, XX, and XXI where applicable.

XIII. Functional Assays

[0351] KAP function is assessed by expressing the sequences encoding KAP at physiologically elevated levels in mammalian cell culture systems. cDNA is subcloned into a mammalian expression vector containing a strong promoter that drives high levels of cDNA expression. Vectors of choice include PCMV SPORT (Life Technologies) and PCR3.1 (Invitrogen, Carlsbad Calif.), both of which contain the cytomegalovirus promoter. 5-10 μg of recombinant vector are transiently transfected into a human cell line, for example, an endothelial or hematopoietic cell line, using either liposome formulations or electroporation. 1-2 μg of an additional plasmid containing sequences encoding a marker protein are co-transfected. Expression of a marker protein provides a means to distinguish transfected cells from nontransfected cells and is a reliable predictor of cDNA expression from the recombinant vector. Marker proteins of choice include, e.g., Green Fluorescent Protein (GFP; Clontech), CD64, or a CD64-GFP fusion protein. Flow cytometry (CM), an automated, laser optics-based technique, is used to identify transfected cells expressing GFP or CD64-GFP and to evaluate the apoptotic state of the cells and other cellular properties. FCM detects and quantifies the uptake of fluorescent molecules that diagnose events preceding or coincident with cell death. These events include changes in nuclear DNA content as measured by staining of DNA with propidium iodide; changes in cell size and granularity as measured by forward light scatter and 90 degree side light scatter; down-regulation of DNA synthesis as measured by decrease in bromodeoxyuridine uptake; alterations in expression of cell surface and intracellular proteins as measured by reactivity with specific antibodies; and alterations in plasma membrane composition as measured by the binding of fluorescein-conjugated Annexin V protein to the cell surface. Methods in flow cytometry are discussed in Ormerod, M. G. (1994) Flow Cytometry, Oxford, New York N.Y.

[0352] The influence of KAP on gene expression can be assessed using highly purified populations of cells transfected with sequences encoding KAP and either CD64 or CD64-GFP. CD64 and CD64-GFP are expressed on the surface of transfected cells and bind to conserved regions of human immunoglobulin G (IgG). Transfected cells are efficiently separated from nontransfected cells using magnetic beads coated with either human IgG or antibody against CD64 (DYNAL, Lake Success N.Y.). mRNA can be purified from the cells using methods well known by those of skill in the art. Expression of mRNA encoding KAP and other genes of interest can be analyzed by northern analysis or microarray techniques.

XIV. Production of KAP Specific Antibodies

[0353] KAP substantially purified using polyacrylamide gel electrophoresis (PAGE; see, e.g., Harrington, M. G. (1990) Methods Enzymol. 182:488-495), or other purification techniques, is used to immunize rabbits and to produce antibodies using standard protocols.

[0354] Alternatively, the KAP amino acid sequence is analyzed using LASERGENE software (DNASTAR) to determine regions of high immunogenicity, and a corresponding oligopeptide is synthesized and used to raise antibodies by means known to those of skill in the art. Methods for selection of appropriate epitopes, such as those near the C-terminus or in hydrophilic regions are well described in the art. (See, e.g., Ausubel, 1995, supra, ch. 11.)

[0355] Typically, oligopeptides of about 15 residues in length are synthesized using an ABI 431A peptide synthesizer (Applied Biosystems) using FMOC chemistry and coupled to KLH (Sigma-Aldrich, St. Louis Mo.) by reaction with N-malemidobenzoyl-N-hydroxysuccinimide ester (MBS) to increase immunogenicity. (See, e.g., Ausubel, 1995, supra.) Rabbits are immunized with the oligopeptide-KLH complex in complete Freund's adjuvant Resulting antisera are tested for antipeptide and anti-KAP activity by, for example, binding the peptide or KAP to a substrate, blocking with 1% BSA, reacting with rabbit antisera, washing, and reacting with radio-iodinated goat anti-rabbit IgG.

XV. Purification of Naturally Occurring KAP Using Specific Antibodies

[0356] Naturally occurring or recombinant KAP is substantially purified by immunoaffinity chromatography using antibodies specific for KAP. An immunoaffinity column is constructed by covalently coupling anti-KAP antibody to an activated chromatographic resin, such as CNBr-activated SEPHAROSE (Amersham Pharmacia Biotech). After the coupling, the resin is blocked and washed according to the manufacturer's instructions.

[0357] Media containing KAP are passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of KAP (e.g., high ionic strength buffers in the presence of detergent). The column is eluted under conditions that disrupt antibody/KAP binding (e.g., a buffer of pH 2 to pH 3, or a high concentration of a chaotrope; such as urea or thiocyanate ion), and KAP is collected.

XVI. Identification of Molecules Which Interact with KAP

[0358] KAP, or biologically active fragments thereof, are labeled with “¹²⁵I Bolton-Hunter reagent. (See, e.g., Bolton, A. E. and W. M. Hunter (1973) Biochem. J. 133:529-539.) Candidate molecules previously arrayed in the wells of a multi-well plate are incubated with the labeled KAP, washed, and any wells with labeled KAP complex are assayed. Data obtained using different concentrations of KAP are used to calculate values for the number, affinity, and association of KAP with the candidate molecules.

[0359] Alternatively, molecules interacting with KAP are analyzed using the yeast two-hybrid system as described in Fields, S. and O. Song (1989) Nature 340:245-246, or using commercially available kits based on the two-hybrid system, such as the MATCHMAKER system (Clontech).

[0360] KAP may also be used in the PATHCALLING process (CuraGen Corp., New Haven Conn.) which employs the yeast two-hybrid system in a high-throughput manner to determine all interactions between the proteins encoded by two large libraries of genes (Nandabalan, K. et al. (2000) U.S. Pat. No. 6,057,101).

XVII. Demonstration of KAP Activity

[0361] Generally, protein kinase activity is measured by quantifying the phosphorylation of a protein substrate by KAP in the presence of [γ-³²P]ATP. KAP is incubated with the protein substrate, ³²P-ATP, and an appropriate kinase buffer. The ³²P incorporated into the substrate is separated from free ³P-ATP by electrophoresis and the incorporated ³²P is counted using a radioisotope counter. The amount of incorporated ³²P is proportional to the activity of KAP. A determination of the specific amino acid residue phosphorylated is made by phosphoamino acid analysis of the hydrolyzed protein.

[0362] In one alternative, protein kinase activity is measured by quantifying the transfer of gamma phosphate from adenosine triphosphate (ATP) to a serine, threonine or tyrosine residue in a protein substrate. The reaction occurs between a protein kinase sample with a biotinylated peptide substrate and gamma ³²P-ATP. Following the reaction, free avidin in solution is added for binding to the biotinylated ³²P-peptide product. The binding sample then undergoes a centrifugal ultrafiltration process with a membrane which will retain the product-avidin complex and allow passage of free gamma ³²P-ATP. The reservoir of the centrifuged unit containing the ³²P-peptide product as retentate is then counted in a scintillation counter. This procedure allows the assay of any type of protein kinase sample, depending on the peptide substrate and kinase reaction buffer selected. This assay is provided in kit form (ASUA, Affinity Ultrafiltration Separation Assay, Transbio Corporation, Baltimore Md., U.S. Pat. No. 5,869,275). Suggested substrates and their respective enzymes include but are not limited to: Histone H1 (Sigma) and p34^(cdc2)kinase, Annexin I, Angiotensin (Sigma) and EGF receptor kinase, Annexin II and src kinase, ERK1 & ERK2 substrates and MEK, and myelin basic protein and ERK (Pearson, J. D. et al. (1991) Methods Enzymol. 200:62-81).

[0363] In another alternative, protein kinase activity of KAP is demonstrated in an assay containing KAP, 50 μl of kinase buffer, 1 μg substrate, such as myelin basic protein (MBP) or synthetic peptide substrates, 1 mM DTT, 10 μg ATP, and 0.5 μCi [γ-³²P)ATP. The reaction is incubated at 30° C. for 30 minutes and stopped by pipetting onto P81 paper. The unincorporated [γ-³²P]ATP is removed by washing and the incorporated radioactivity is measured using a scintillation counter. Alternatively, the reaction is stopped by heating to 100° C. in the presence of SDS loading buffer and resolved on a 12% SDS polyacrylamide gel followed by autoradiography. The amount of incorporated ³²P is proportional to the activity of KAP.

[0364] In yet another alternative, adenylate kinase or guanylate kinase activity of KAP may be measured by the incorporation of ³²P from [γ-³²P]ATP into ADP or GDP using a gamma radioisotope counter. KAP, in a kinase buffer, is incubated together with the appropriate nucleotide mono-phosphate substrate (AMP or GMP) and ³²P-labeled ATP as the phosphate donor. The reaction is incubated at 37° C. and terminated by addition of trichloroacetic acid. The acid extract is neutralized and subjected to gel electrophoresis to separate the mono, di-, and triphosphonucleotide fractions. The diphosphonucleotide fraction is excised and counted. The radioactivity recovered is proportional to the activity of KAP.

[0365] In yet another alternative, other assays for KAP include scintillation proximity assays (SPA), scintillation plate technology and filter binding assays. Useful substrates include recombinant proteins tagged with glutathione transferase, or synthetic peptide substrates tagged with biotin. Inhibitors of KAP activity, such as small organic molecules, proteins or peptides, may be identified by such assays.

[0366] In another alternative, phosphatase activity of KAP is measured by the hydrolysis of para-nitrophenyl phosphate (PNPP). KAP is incubated together with PNPP in HEPES buffer pH 7.5, in the presence of 0.1% β-mercaptoethanol at 37° C. for 60 min. The reaction is stopped by the addition of 6 ml of 10 N NaOH (Diamond, R. H. et al. (1994) Mol. Cell. Biol. 14:3752-62). Alternatively, acid phosphatase activity of KAP is demonstrated by incubating KAP-containing extract with 100 μl of 10 mM PNPP in 0.1 M sodium citrate, pH 4.5, and 50 μl of 40 mM NaCl at 37° C. for 20 min. The reaction is stopped by the addition of 0.5 ml of 0.4 M glycine/NaOH, pH 10.4 (Saftig, P. et al. (1997) J. Biol. Chem 272:18628-18635). The increase in light absorbance at 410 nm resulting from the hydrolysis of PNPP is measured using a spectrophotometer. The increase in light absorbance is proportional to the activity of KAP in the assay.

[0367] In the alternative, KAP activity is determined by measuring the amount of phosphate removed from a phosphorylated protein substrate. Reactions are performed with 2 or 4 nM KAP in a final volume of 30 μl containing 60 mM Tris, pH 7.6, 1 mM EDTA, 1 mM EGTA, 0.1% β-mercaptoethanol and 10 μM substrate, ³²P-labeled on serine/threonine or tyrosine, as appropriate. Reactions are initiated with substrate and incubated at 30° C. for 10-15 min. Reactions are quenched with 450 μl of 4% (w/v) activated charcoal in 0.6 M HCl, 90 mM Na₄P₂O₇, and 2 mM NaH₂PO₄, then centrifuged at 12,000×g for 5 min. Acid-soluble ³Pi is quantified by liquid scintillation counting (Sinclair, C. et al. (1999) J. Biol. Chem. 274:23666-23672).

XVIII. Kinase Binding Assay

[0368] Binding of KAP to a FLAG-CD44 cyt fusion protein can be determined by incubating KAP with anti-KAP-conjugated immunoaffinity beads followed by incubating portions of the beads (having 10-20 ng of protein) with 0.5 ml of a binding buffer (20 mM Tris-HCL (pH 7.4), 150 mM NaCl, 0.1% bovine serum albumin, and 0.05% Triton X-100) in the presence of ¹²⁵I-labeled FLAG-CD44cyt fusion protein (5,000 cpm/ng protein ) at 4° C. for 5 hours. Following binding, beads were washed thoroughly in the binding buffer and the bead-bound radioactivity measured in a scintillation counter (Bourguignon, L. Y. W. et al. (2001) J. Biol. Chem 276:7327-7336). The amount of incorporated ³²P is proportional to the amount of bound KAP.

XIX. Identification of KAP Inhibitors

[0369] Compounds to be tested are arrayed in the wells of a 384-well plate in varying concentrations along with an appropriate buffer and substrate, as described in the assays in Example XVII. KAP activity is measured for each well and the ability of each compound to inhibit KAP activity can be determined, as well as the dose-response kinetics. This assay could also be used to identify molecules which enhance KAP activity.

XX. Identification of KAP Substrates

[0370] A KAP “substrate-trapping” assay takes advantage of the increased substrate affinity that may be conferred by certain mutations in the PTP signature sequence of protein tyrosine phosphatases. KAP bearing these mutations form a stable complex with their substrate; this complex may be isolated biochemically. Site-directed mutagenesis of invariant residues in the PTP signature sequence in a clone encoding the catalytic domain of KAP is performed using a method standard in the art or a commercial kit, such as the MUTA-GENE kit from BIO-RAD. For expression of KAP mutants in Escherichia coli, DNA fragments containing the mutation are exchanged with the corresponding wild-type sequence in an expression vector bearing the sequence encoding KAP or a glutathione S-transferase (GST)-KAP fusion protein. KAP mutants are expressed in E. coli and purified by chromatography.

[0371] The expression vector is transfected into COS1 or 293 cells via calcium phosphate-mediated transfection with 20 μg of CsCl-purified DNA per 10-cm dish of cells or 8 μg per 6cm dish. Forty-eight hours after transfection, cells are stimulated with 100 ng/ml epidermal growth factor to increase tyrosine phosphorylation in cells, as the tyrosine kinase EGFR is abundant in COS cells. Cells are lysed in 50 mM TrisHCl, pH 7.5/5 mM EDTA/150 mM NaCl/1% Triton X-100/5 mM iodoacetic acid/10 mM sodium phosphate/10 mM NaF/5 μg/ml leupeptin/5 μg/ml aprotinin/1 mM benzamidine (1 ml per 10-cm dish, 0.5 ml per 6-cm dish). KAP is immunoprecipitated from lysates with an appropriate antibody. GST-KAP fusion proteins are precipitated with glutathione-Sepharose, 4 μg of mAb or 10 μl of beads respectively per mg of cell lysate. Complexes can be visualized by PAGE or further purified to identify substrate molecules (Flint, A. J. et al. (1997) Proc. Natl. Acad. Sci. USA 94:1680-1685).

XXI. Enhancement/Inhibition of Protein Kinase Activity

[0372] Agonists or antagonists of KAP activation or inhibition may be tested using assays described in section XVII. Agonists cause an increase in KAP activity and antagonists cause a decrease in KAP activity.

[0373] Various modifications and variations of the described methods and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with certain embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in molecular biology or related fields are intended to be within the scope of the following claims. TABLE 1 Polynucleo- Incyte Incyte Polypeptide Incyte tide SEQ Polynucleo- Project ID SEQ ID NO: Polypeptide ID ID NO: tide ID 4615110 1 4615110CD1 21 4615110CB1 4622229 2 4622229CD1 22 4622229CB1 72358203 3 72358203CD1 23 72358203CB1 4885040 4 4885040CD1 24 4885040CB1 7484507 5 7484507CD1 25 7484507CB1 7198931 6 7198931CD1 26 7198931CB1 7482905 7 7482905CD1 27 7482905CB1 7483019 8 7483019CD1 28 7483019CB1 5455490 9 5455490CD1 29 5455490CB1 5547067 10 5547067CD1 30 5547067CB1 71675660 11 71675660CD1 31 71675660CB1 71678683 12 71678683CD1 32 71678683CB1 7474567 13 7474567CD1 33 7474567CB1 3838946 14 3838946CD1 34 3838946CB1 72001176 15 72001176CD1 35 72001176CB1 55064363 16 55064363CD1 36 55064363CB1 7482044 17 7482044CD1 37 7482044CB1 7476595 18 7476595CD1 38 7476595CB1 71824382 19 71824382CD1 39 71824382CB1 3566882 20 3566882CD1 40 3566882CB1

[0374] TABLE 2 Incyte GenBank ID NO: Polypeptide Polypeptide or PROTEOME Probability SEQ ID NO: ID ID NO: Score Annotation 1 4615110CD1 g3598974 0 [Rattus norvegicus] protein tyrosine phosphatase TD14. Cao, L. et al. (1998) J. Biol. Chem. 273: 21077-21083 2 4622229CD1 g4079673 0 myotubularin related 1 [Homo sapiens]. Kioschis, P. et al. (1998) Genomics 54: 256-266 3 72358203CD1 g7768151 6.40E−17  Protein phosphatase 2C (PP2C) [Fagus sylvatica]. 4 4885040CD1 g6468206 1.20E−119 [Mus musculus] thiamin pyrophosphokinase. Nosaka, K. et al. (1999) J. Biol. Chem. 274: 34129-34133 5 7484507CD1 g7649810 7.20E−14  [Homo sapiens] protein kinase PAK5 6 7198931CD1 g2815888 0 [Homo sapiens] MEK kinase 1. Xia, Y. et al. (1998) Genes Dev. 12: 3369-3381 7 7482905CD1 g256855 2.10E−161 [Mus sp.] serine/threonine-and tyrosine-specific protein kinase, Nek1 = NIMA cell cycle regulator homolog. Letwin, K., et al. (1992) EMBO J. 11: 3521-3531 8 7483019CD1 g6552404 8.40E−197 [Rattus norvegicus] DLG6 alpha. Inagaki, H. et al. (1999) Biochem. Biophys. Res. Commun. 265: 462-468 9 5455490CD1 g406058 0 protein kinase [Mus musculus]. (Walden, P. D. and Cowan, N. J. (1993) Mol. Cell. Biol. 13: 7625-7635) 10 5547067CD1 g1033033 5.90E−41  ribosomal S6 kinase [Homo sapiens]. (Zhao, Y. et al. (1995) Mol. Cell. Biol. 15: 4353-4363) 11 71675660CD1 g2738898 9.40E−175 protein kinase [Mus musculus]. (Kueng, P. et al. (1997) J. Cell Biol. 139: 1851-1859) 12 71678683CD1 g2738898 4.00E−174 protein kinase [Mus musculus]. (Kueng, P. et al. (1997) J. Cell Biol. 139: 1851-1859) 13 7474567CD1 p6723964 2.50E−72  putative serine/threonine protein kinase [Schizosaccharomyces pombe] 14 3838946CD1 g4982155 2.80E−53  glycerate kinase, putative [Thermotoga maritima]. (Nelson, K. E. et al. (1999) Nature 399: 323-329) 15 72001176CD1 g11177010 5.70E−232 casein kinase 1 gamma 1L [Homo sapiens] 16 55064363CD1 g1679668 0 Mitogen-activated kinase kinase 5 [Homo sapiens] (Wang, X. S. et al. (1996) J. Biol. Chem. 271: 31607-31611) 17 7482044CD1 g11527775 0 Mitogen-activated protein kinase kinase kinase [Homo sapiens] 18 7476595CD1 g406058 0 [Mus musculus] protein kinase. Walden, P. D. and Cowan, N. J. (1993) A Novel 205-kDa Testis-specific Serine/Threonine Protein kinase Associated with Microtubules of the Spermatid Manchette. Mol. Cell. Biol. 13, 7625-7635

[0375] TABLE 3 Ami- no SEQ Acid Analytical ID Incyte Resi- Potential Potential Methods and NO: Polypeptide ID dues Phosphorylation Sites Glycosylation Sites Signature Sequences, Domains and Motifs Databases 1 4615110CD1 1636 S86 S101 S136 S193 N652 N1245 N1634 Protein-tyrosine phosphatase: Y1217-R1451 HMMER_PFAM S275 S311 S429 S455 S487 S546 S645 S869 S1056 S1122 S1218 S1231 S1238 S1247 S1290 S1322 S1342 S1475 S1506 S1533 S1575 S1593 S1625 T95 T293 T352 T434 T450 T486 T511 T882 T1068 T1144 T1269 T1305 T1328 T1354 Y272 Y320 Y1165 Y1229 Tyrosine specific protein phosphatases proteins BLIMPS_(—) BL00383: K1220-V1234, D1241-V1249, D1272- BLOCKS V1282, H1349-P1361, V1390-G1400, R1429- F1444 Tyrosine specific protein phosphatases signature and PROFILESCAN profiles: L1367-M1428 Protein tyrosine phosphatase signature PR00700: BLIMPS_(—) D1242-V1249, I1259-E1279, R1345-D1362, P1387- PRINTS L1405, P1419-H1434, M1435-C1445 PROTEIN TYROSINE PHOSPHATASE TD14 EC BLAST_(—) 3.1.3.48 HYDROLASE PD180360: F967-L1219 PRODOM PROTEIN TYROSINE PHOSPHATASE TD14 EC BLAST_(—) 3.1.3.48 HYDROLASE PD184907: K713-G952 PRODOM PROTEIN TYROSINE PHOSPHATASE TD14 EC BLAST_(—) 3.1.3.48 HYDROLASE PD169419: A1567-T1636 PRODOM PROTEIN-TYROSINE-PHOSPHATASE BLAST_DOMO DM00089|P17706|4-277: K1220-V1450 PROTEIN-TYROSINE-PHOSPHATASE BLAST_DOMO DM00089|P26045|632-904: K1220-Q1455 PROTEIN-TYROSINE-PHOSPHATASE BLAST_DOMO DM00089|P29074|641-914: K1220-Q1455 PROTEIN-TYROSINE-PHOSPHATASE BLAST_DOMO DM00089|P43378|285-577: K1220-Q1455 Tyrosine specific protein phosphatases active site: MOTIFS V1390-F1402 2 4622229CD1 673 S53 S113 S163 S172 N78 N251 N359 Transmembrane domains: W517-S543; N-terminus TMAP S225 S253 S261 is cytosolic S278 S342 S354 S391 S402 S410 S437 S525 S575 S600 S654 S656 T136 T334 T358 T470 T476 T536 Y331 Y400 Y563 Tyrosine specific protein phosphatases proteins BLIMPS_(—) BL00383: W570-D578, Q511-R521, V444-A454 BLOCKS Tyrosine specific protein phosphatases signature and PROFILESCAN profiles: L424-K480 HYDROLASE PROTEIN MYOTUBULARIN BLAST_(—) DISEASE MUTATION F53A2.8 PROTEIN PRODOM TYROSINE PHOSPHATASE C19A8.03 CPA2NNF1 PD014611: C178-Y372, D504-H591 MYOTUBULARIN DISEASE MUTATION BLAST_(—) HYDROLASE PD144999: H601-T671 PRODOM Tyrosine specific protein phosphatases active site: MOTIFS V444-L456 3 72358203CD1 459 S50, T257, T278, Protein phosphatase 2C: Q326-K415, L187-L265 HMMER-PFAM S306, T364, S430, S438 Protein phosphatase 2C: BL01032: Y120-G129, BLIMPS_(—) L187-G204, G214-S223, N232-E271, R328-D341, BLOCKS D376-D388 PROTEIN PHOSPHATASE 2C MAGNESIUM BLAST_(—) HYDROLASE MANGANESE MULTIGENE PRODOM FAMILY PP2C ISOFORM: PD001101: G322- L403, Y120-D289 PROTEIN PHOSPHATASE 2C: BLAST-DOMO DM00377|P49596|1-295: A191-I262, R328-S456, Y120-E149 4 4885040CD1 243 S74 S92 T6 T56 N203 Ribokinase signature PR00990 V121-F132 BLIMPS_(—) T176 PRINTS THIAMIN PYROPHOSPHOKINASE PUTATIVE BLAST_(—) TPK KINASE, PD106295: H170-M239; PRODOM PD036502: L21-Q144 5 7484507CD1 632 S6 S20 S114 S212 N208 Eukaryotic protein kinase domain: V55-L173, W201- HMMER_PFAM S231 S244 S251 L297 S283 S300 S318 S504 S575 S587 S601 S607 T12 T183 T258 T269 T287 T338 T418 Transmembrane domains: E421-N448 M472-G487, TMAP N terminus cytosolic Tyrosine kinase catalytic domain PROO109, Y147- BLIMPS_(—) L165, F197-L207, S215-E237 PRINTS PHOSPHORYLASE KINASE ALP PD01841: L422- BLIMPS_(—) L458, A464-I505, G567-L603, E23-E72, L142- PRODOM E193 PROTEIN KINASE DOMAIN DM00004; BLAST_DOMO P51955|10-261: V30-M233; S43968|28-311: Q33- K289, R271-I288 A55480|28-320: Q33-K289, R271- L297; P49186|28-320: Q33-K289, R271-L297 6 7198931CD1 1511 S35 S118 S232 S258 N346 N540 N744 Eukaryotic protein kinase domain: W1242-F1507 HMMER_PFAM S275 S281 S300 N806 N1068 N1085 S394 S397 S398 N1099 N1128 S429 S434 S507 N1278 N1347 S514 S531 S588 S669 S782 S816 S823 S900 S923 S928 S1025 S1038 S1087 S1088 S1129 S1130 S1281 T20 T169 T261 T304 T379 T457 T657 T705 T911 T946 T996 T1020 T1069 T1113 T1147 T1165 T1279 Y1166 Transmembrane domains: S348-L368, A1392- TMAP L1420; N-terminus is cytosolic Protein kinases signatures and profile: V1344- PROFILESCAN G1398 Tyrosine kinase catalytic domain signature BLIMPS_(—) PR00109: L1476-S1498, Y1358-I1376, G1410-L1420, PRINTS C1429-E1451 MAPK/ERK KINASE 1 EC 2.7.1. MEK MEKK BLAST_(—) TRANSFERASE SERINE/THREONINE PRODOM PROTEIN ATP BINDING PHOSPHORYLATION PD144583: M1-E601 MAPK/ERK KINASE 1 EC 2.7.1. MEK MEKK BLAST_(—) TRANSFERASE SERINE/THREONINE PRODOM PROTEIN ATP BINDING PHOSPHORYLATION PD146039: Q624-Q1247 PROTEIN KINASE DOMAIN BLAST_DOMO DM00004|P53349|405-658: K1244-S1498 PROTEIN KINASE DOMAIN BLAST_DOMO DM00004|A48084|98-348: K1244-R1495 PROTEIN KINASE DOMAIN BLAST_DOMO DM00004|Q01389|1176-1430: L1243-P1496 PROTEIN KINASE DOMAIN BLAST_DOMO DM00004|Q10407|826-1084: L1243-L1488 Protein kinases ATP-binding region signature: I1248- MOTIFS K1271 Serine/Threonine protein kinases active-site MOTIFS signature: I1364-I1376 7 7482905CD1 830 S54 S179 S260 S279 N159 N303 N401 signal_cleavage: M1-S54 SPSCAN S280 S327 S352 N540 N715 S370 S378 S440 S457 S525 S545 S580 S624 S664 S698 S708 S741 S747 T267 T354 T358 T403 T481 T490 T512 T634 T640 T674 SERINE/THREONINE PROTEIN KINASE NEK1 BLAST_(—) EC 2.7.1. NIMA RELATED PROTEIN 1 PRODOM TRANSFERASE ATP BINDING MITOSIS NUCLEAR PHOSPHORYLATION CELL CYCLE DIVISION TYROSINE PROTEIN PD144030: M1- L394 8 7483019CD1 455 S142 S200 S208 N419 Guanylate kinase: T281-Y385 HMMER_PFAM S242 S308 S374 S421 S450 T16 T280 T283 Y307 Y317 Y359 PDZ domain: I3-V83 HMMER_PFAM Guanylate kinase protein BL00856: BLIMPS_(—) BLOCKS SH3 domain signature PR00452: A115-Q130, D132- BLIMPS_(—) I141, C147-R159 PRINTS PROTEIN DOMAIN SH3 KINASE GUANYLATE BLAST_(—) TRANSFERASE ATP BINDING REPEAT GMP PRODOM MEMBRANE PD001338: T280-Q373 PROTEIN MAGUK P55 SUBFAMILY MEMBER BLAST_(—) MPP3 DISCS LARGE HOMOLOG SH3 PRODOM PD090357: P169-T280 PROTEIN MAGUK P55 SUBFAMILY MEMBER BLAST_(—) DISCS LARGE HOMOLOG SH3 DOMAIN PRODOM PD152180: V94-Q161 GUANYLATE KINASE DM00755|A57653|370-570: BLAST_DOMO P241-P444 GUANYLATE KINASE DM00755|P54936|769-955: BLAST_DOMO R246-K372, M388-P444 GUANYLATE KINASE DM00755|I38757|709-898: BLAST_DOMO R246-P444 GUANYLATE KINASE DM00755|P31007|765-954: BLAST_DOMO R246-P444 Guanylate kinase signature: T280-V297 MOTIFS 9 5455490CD1 1720 S75 S82 S86 S115 N1115 N1174 Signal Peptide: M1-S68 SPSCAN S119 S140 S152 N1215 S175 S203 S402 S425 S430 S455 S697 S728 S733 S739 S747 S768 S776 S782 S796 S831 S836 S853 S1006 S1022 S1117 S1127 S1136 S1147 S1151 S1152 S1178 S1194 S1254 S1259 S1340 S1347 S1351 S1369 S1381 S1413 S1425 S1426 S1463 S1572 S1579 S1582 S1593 S1620 S1639 S1693 T188 T428 T436 T487 T503 T651 T681 T708 T737 T793 T838 T847 T871 T936 T958 T962 T1039 T1111 T1158 T1166 T1346 T1402 T1597 T1687 Signal Peptide: M31-S56 HMMER PDZ domain (or DHR, or GLGF): P1026-L1113 HMMER_PFAM Eukaryotic protein kinase domain: F434-F707 HMMER_PFAM Transmembrane domains: V328-E350, D629- TMAP F647; N terminus is cytosolic. Protein kinases signatures and profile: F501-I581 PROFILESCAN Tyrosine kinase catalytic domain sig. PR00109: BLIMPS_(—) M511-K524, Y547-I565, V628-D650 PRINTS MICROTUBULE ASSOCIATED TESTIS BLAST_(—) SPECIFIC SERINE/THREONINE KINASE PRODOM PD142315: H1235-T1720; PD182663: E785-H1061; PD135564: C83-Y242; PD041650: K243- D433 PROTEIN KINASE DOMAIN: BLAST_DOMO DM00004|A54602|455-712: T436-G694; DM08046|P05986|1-397: S430-K580; DM00004|S42867|75-498: I437-T588; DM00004|S42864|41-325: E435-K580, H594- T695 Serine/Threonine protein kinases active-site MOTIFS signature: I553-I565 10 5547067CD1 449 S17 S45 S89 S107 Eukaryotic protein kinase domain: L146-F398 HMMER_PFAM S208 S244 S358 S425 T86 T167 T187 T337 T356 Transmembrane domains: S244-R267, D324-P341; TMAP N terminus is cytosolic. Protein kinases signatures and profile: F248-A297 PROFILESCAN Tyrosine kinase catalytic domain signature, BLIMPS_(—) PR00109: Y258-L276, G304-L314, A323-E345 PRINTS PROTEIN KINASE DOMAIN: BLAST_DOMO DM00004|A53300|64-305: L146-L386; DM08046|P06244|1-396: Q144-F435; DM00004|A57459|61-302: L146-L386; DM00004|S56639|153-391: I148-L386 Serine/Threonine protein kinases active-site MOTIFS signature: I264-L276 11 71675660CD1 358 S31 S158 S258 S284 N240 Eukaryotic protein kinase domain: Y12-L272 HMMER_PFAM S349 T48 T340 Y293 Transmembrane domain: V196-M224; N terminus TMAP is non-cytosolic. Protein kinases signatures and profile: D111-S165 PROFILESCAN Tyrosine kinase catalytic domain signature: BLIMPS_(—) PR00109: M90-K103, Y126-L144, L241-I263 PRINTS TESTIS SPECIFIC SERINE/ THREONINE BLAST_(—) KINASE 2 PROTEIN KINASE; PD029090: L272- PRODOM T358 PROTEIN KINASE DOMAIN: BLAST_DOMO DM00004|P27448|58-297: L18-L253; DM00004|JC1446|20-261: V14-I263; DM00004|S24578|18-262: V14-I263; DM00004|I48609|55-294: L18-R260 Serine/Threonine protein kinases active-site MOTIFS signature: I132-L144 Protein kinases ATP-binding region signature: L18- MOTIFS K41 12 71678683CD1 358 S31 S158 S258 S284 N240 Eukaryotic protein kinase domain: Y12-L272 HMMER_PFAM S349 T48 T340 Y293 Transmembrane domain: V196-M224; N terminus TMAP is non-cytosolic. Protein kinases signatures and profile: D111-S165 PROFILESCAN Tyrosine kinase catalytic domain signature, BLIMPS_(—) PR00109: M90-K103, Y126-L144, G177-L187, PRINTS Y197-S219, L241-I263 TESTIS SPECIFIC SERINE/THREONINE BLAST_(—) KINASE 2 PROTEIN KINASE, PD029090: L272- PRODOM T358 PROTEIN KINASE DOMAIN: BLAST_DOMO DM00004|P27448|58-297: L18-L253; DM00004|JC1446|20-261: V14-I263; DM00004|S24578|18-262: V14-I263; DM00004|I48609|55-294: L18-R260 Serine/Threonine protein kinases active-site MOTIFS signature: I132-L144 Protein kinases ATP-binding region signature: L18- MOTIFS K41 13 7474567CD1 929 S56 S85 S171 S207 N51 N187 N630 Eukaryotic protein kinase domain: L159-F327, F32- HMMER_PFAM S483 S660 S677 T53 N726 N768 N916 H106 T57 T245 T313 T401 T440 T555 T608 T658 T679 T712 T722 T737 T760 T765 Tyrosine kinase catalytic domain signature, BLIMPS_(—) PR00109: L168-L186, S247-V269, I296- PRINTS A318 14 3838946CD1 523 S283 S289 S367 N487 Transmembrane domain: E163-L183, N-terminus TMAP S417 T166 T191 is non-cytosolic T208 T214 Y328 HYDROXYPYRUVATE REDUCTASE PLASMID BLAST_(—) OXIDOREDUCTASE NADP PROTEIN PRODOM GLYCERATE KINASE, PD014236: K131-T357, T357-L520 15 72001176CD1 459 S96 S124 S150 S229 N370 N388 Eukaryotic protein kinase domain: F44-E276 HMMER_PFAM S373 T14 T137 T199 T214 T258 T269 T273 T355 T411 T454 Transmembrane domain: D133-I161 N-terminus is TMAP cytosolic. Protein kinases signatures and profile: T140-E198 PROFILESCAN CASEIN KINASE I, GAMMA 1 ISOFORM EC BLAST_(—) 2.7.1. GAMMA TRANSFERASE PRODOM SERINE/THREONINE ATP BINDING MULTIGENE FAMILY PHOSPHORYLATION; PD049080: M1-N43, PD015080: F315-W379 PROTEIN KINASE DOMAIN: BLAST_DOMO DM00004|A56711|46-303: V46-Y304; DM00004|C56711|45-301: V46-Y304; DM00004|B56711|48-303: V46-Y304; DM00004|D56406|31-276: V46-V293 Protein kinases ATP-binding region signature: I50- MOTIFS K73 Serine/Threonine protein kinases active-site MOTIFS signature: L160-I172 16 55064363CD1 1360 S23 S56 S212 S253 N381 N620 Eukaryotic protein kinase domain: V704-L955 HMMER-PFAM S338 S382 S432 S486 S550 S609 S625 S632 S655 S677 S762 S843 S934 S991 S1025 S1031 S1040 S1041 S1056 S1084 T48 T205 T218 T428 T466 T545 T685 T796 T842 T887 T893 T945 T983 T1234 T1287 T1314 T1323 Y810 Y1313 Transmembrane domains: S445-T466, S1129- TMAP V1146; N-terminus is cytosolic Protein kinases signature: T796-G848 ProfileScan Protein kinases ATP-binding region signature: L705- MOTIFS K728 Serine/Threonine protein kinases active-site MOTIFS signature: I816-V828 Tyrosine kinase catalytic domain signature BLIMPS-PRINTS PR00109: M773-R786, Y810-V828, G858- I868, A879-L901, L924-T946 Kinase, apoptosis, ASK1, MEK signal-regulating, BLAST_(—) mitogen-activated, MEKK5, MAP/ERK, PRODOM MAPKKK5 PD018410: V75-N620 Kinase, apoptosis, ASK1, MEK signal-regulating, BLAST_(—) mitogen-activated, MEKK5, MAP/ERK, PRODOM MAPKKK5 PD014104: P982-G1205 Kinase, apoptosis, ASK1, MEK signal-regulating, BLAST_(—) mitogen-activated, MEKK5, MAP/ERK, PRODOM MAPKKK5 PD024456: E1215-R1348 Kinase, apoptosis, ASK1, MEK signal-regulating, BLAST_(—) mitogen-activated, MEKK5, MAP/ERK, PRODOM MAPKKK5 PD012471: F621-D697 Protein kinase domains: DM00004|A48084|98-348: BLAST-DOMO V704-R943; DM00004|Q01389|1176-1430: V704- T945; DM00004|Q10407|826-1084: V704-T945; DM00004|P41892|11-249: L705-T946 17 7482044CD1 1345 S31 S35 S191 S250 Eukaryotic protein kinase domain: L181-F439 HMMER-PFAM S323 S338 S517 S600 S625 S1131 S1160 S1165 T67 T136 T154 T174 T203 T218 T268 T333 T396 T459 T492 T1161 T1201 T1231 T1251 T1273 T1294 Y428 Transmembrane domain: A868-A890; N-terminus is TMAP cytosolic Protein kinases signature: L284-F339 ProfileScan Serine/Threonine protein kinases active-site MOTIFS signature: I305-I317 Leucine zipper pattern: L826-L847 MOTIFS Protein kinase domains: DM00004|A48084|98-348: BLAST-DOMO V704-R943; DM00004|Q01389|1176-1430: V704- T945; DM00004|Q10407|826-1084: V704-T945; DM00004|P41892|11-249: L705- T946; DM00004|P51957|8-251: L187-R427, DM00004|P41892|11-249: L187-V395, DM00004|Q05609|553-797: E186-C419 18 7476595CD1 2038 S18 S28 S324 S329 N16 N645 N703 PDZ domain (Also known as DHR or GLGF): Q555- HMMER_PFAM S335 S365 S407 N740 N1266 F643 S448 S536 S562 N1282 N1473 S647 S657 S666 S669 S674 S680 S707 S721 S728 S731 S780 S785 S871 S878 S882 S895 S903 S930 S938 S974 S1000 S1007 S1027 S1073 S1109 S1182 S1199 S1231 S1262 S1270 S1278 S1305 S1340 S1389 S1398 S1514 S1517 S1574 S1583 S1590 S1606 S1629 S1650 S1660 S1745 S1863 S1879 S1899 S1913 S1938 S1960 S2028 T32 T83 T99 T247 T333 T343 T349 T435 T465 T511 T569 T641 T695 T886 T1059 T1079 T1177 T1184 T1321 T1327 T1395 T1407 T1420 T1436 T1554 T1692 T1753 T1769 T1780 T1790 T1844 T1931 T1971 T2006 Y1794 Eukaryotic protein kinase domain: F30-F303 HMMER_PFAM TMAP: D225-F243; N-terminus is cytosolic TMAP Protein kinases signatures and profile protein: F97- PROFILESCAN V177 Tyrosine kinase catalytic domain signature BLIMPS_(—) PR00109: M107-K120, Y143-V161, V224-D246, PRINTS P269-T291 MICROTUBULE ASSOCIATED TESTIS BLAST_(—) SPECIFIC SERINE/THREONINE PROTEIN PRODOM KINASE 205 KD TESTISSPECIFIC SERINE/THREONINE PROTEIN KINASE MAST205 KINASE, PD142315: H760-A1021, P1578-P1716, P1498-P1609, PD069998: T639-D734, PD182663: E499-N591 PROTEIN KINASE SERINE/THREONINE KIN4 BLAST_(—) MICROTUBULE ASSOCIATED TESTIS PRODOM SPECIFIC TESTISSPECIFIC MAST205, PD040805: L306-N374 PROTEIN KINASE DOMAIN; BLAST_DOMO DM00004|A54602|455-712: T32-G290; DM00004|S42867|75-498: I33-K176, H190-F331; DM08046|P05986|1-397: S28-K176, V203-D351; DM08046|P06244|1-396: D29-K176, V203-F354 ATP/GTP-binding site motif A (P-loop): A1450- MOTIFS T1457 Serine/Threonine protein kinases active-site MOTIFS signature: I149-V161 19 71824382CD1 1770 S167 S286 S344 N560 N792 N854 CNH domain: K1266-K1550 HMMER_PFAM S364 S369 S411 N1680 N1739 S459 S475 S507 N1742 S555 S616 S705 S750 S752 S781 S813 S877 S884 S917 S926 S940 S977 S997 S1013 S1193 S1322 S1334 S1357 S1457 S1568 S1583 S1658 S1673 S1694 S1702 S1731 S1751 T30 T64 T423 T591 T624 T691 T746 T780 T788 T959 T1011 T1032 T1050 T1121 T1223 T1293 T1543 T1763 Y358 Y1252 Phorbol esters/diacylglycerol binding domain: HMMER_PFAM H1051-C1100 PH domain: T1121-K1239 HMMER_PFAM Eukaryotic protein kinase domain: F77-F343 HMMER_PFAM Protein kinase C terminal domain: S344-D372 HMMER_PFAM Phorbol esters/diacylglycerol binding domain PROFILESCAN dag_pe_binding_domain: C1064-A1122 Tyrosine kinase catalytic domain signature BLIMPS_(—) PR00109: M154-S167, S191-M209, C263-E285 PRINTS Domain found in NIK1-lik BLIMPS_PFAM PF00780B: I738-T780 PF00780F: T1050-A1096 PF00780G: K1195-H1238 FF00780I: M1485-N1514 MYTONIC DYSTROPHY KINASE-RELATED BLAST_(—) CDC42-BINDING KINASE PHORBOLESTER PRODOM BINDING KIAA0451 PROTEIN PD143271: R1643-P1770 MYTONIC DYSTROPHY KINASE-RELATED BLAST_(—) CDC42-BINDING KINASE PHORBOLESTER PRODOM BINDING PD075023: E630-N713 PHORBOLESTER BINDING KINASE BLAST_(—) DYSTROPHY KINASE-RELATED CDC42- PRODOM BINDING SIMILAR SERINE/THREONINE PROTEIN GENGHIS KHAN PD150840: W1518- S1642 PHORBOLESTER BINDING DYSTROPHY BLAST_(—) KINASE-RELATED CDC42-BINDING KINASE PRODOM GENGHIS KHAN MYTONIC MYOTONIC PD011252: D833-F967 PROTEIN KINASE DOMAIN DM00004; BLAST_DOMO |Q09013|83-336: I79-Q331; |S42867|75-498: I79- L226, V238-Y404, P1653-D1728; |I38133|90-369: E78-L226, V238-G330; |P53894|353-658: L80- G221, D205-Q331 Leucine zipper pattern L772-L793 L779-L800 L786- MOTIFS L807 C-type lectin domain signature C1067-C1088 MOTIFS Phorbol esters/diacylglycerol binding domain MOTIFS H1051-C1100 Protein kinases ATP-binding region signature I83- MOTIFS K106 Serine/Threonine protein kinases active-site MOTIFS signature Y197-M209 20 3566882CD1 720 S91 S117 S146 S148 Ank repeat: E448-R480, D382-R414, V580-Q612, HMMER_PFAM S264 S268 S299 E415-A447, N481-Q513, S349-E381, Q547-A579, S690 S697 T17 T166 S613-K645, V646-G678 T398 Y314 Eukaryotic protein kinase domain: S156-P231 HMMER_PFAM Transmembrane domain: S146-Y171 TMAP Tyrosine kinase catalytic domain signature BLIMPS_(—) PR00109: M94-S107, L152-L174, E211-F233 PRINTS

[0376] TABLE 4 Polynucleotide SEQ ID NO:/ Incyte ID/ Sequence Length Sequence Fragments 21/4615110CB1/ 1-224, 1-277, 4-272, 14-161, 14-225, 42-679, 43-503, 43-609, 43-708, 43-714, 43-872, 48-688, 124-438, 178-4215, 199-420, 5200 200-720, 240-549, 352-679, 355-637, 355-756, 371-754, 374-992, 446-992, 459-1093, 506-1102, 545-827, 564-824, 763-1296, 825-1296, 869-1286, 869-1296, 870-1296, 958-1636, 1046-1625, 1049-1527, 1063-1697, 1098-1689, 1103-1299, 1103-1774, 1133-1736, 1250-1743, 1250-1768, 1250-1840, 1312-1857, 1376-1857, 1416-1857, 1426-1857, 1429-1857, 1496-2036, 1508-1998, 1515-2107, 1554-2211, 1635-2249, 1713-2241, 1716-2315, 1728-2380, 1775-2322, 1796-2438, 1809-2049, 2006-5055, 2020-2679, 2029-2385, 2056-2732, 2069-2702, 2107-2752, 2186-2443, 2196-2638, 2231-2580, 2232-2698, 2271-2775, 2287-2580, 2302-2741, 2335-2806, 2407-2857, 2409-2669, 2432-2980, 2796-2997, 2799-2997, 2810-3016, 2824-2994, 2950-3400, 3029-3604, 3029-3684, 3064-3648, 3100-3372, 3139-3684, 3186-3766, 3194-3457, 3212-3473, 3219-3456, 3228-3737, 3234-3704, 3236-3485, 3236-3719, 3245-3503, 3273-3839, 3273-3887, 3295-3689, 3317-3583, 3317-3604, 3317-3939, 3341-3634, 3351-3979, 3357-3615, 3375-3621, 3396-3971, 3428-4081, 3454-4092, 3475-4060, 3479-4086, 3488-4156, 3491-3759, 3511-3828, 3511-3977, 3540-3825, 3540-3985, 3540-4047, 3548-3834, 3550-4216, 3580-3916, 3590-3928, 3599-4202, 3611-4211, 3627-4351, 3629-4099, 3629-4339, 3630-3907, 3630-4382, 3634-4382, 3641-4215, 3645-3920, 3649-3932, 3649-3933, 3650-3889, 3651-3904, 3654-4181, 3654-4215, 3660-4212, 3662-4080, 3664-4226, 3667-4162, 3667-4210, 3672-4212, 3675-4215, 3683-4211, 3693-4230, 3704-4211, 3706-4173, 3712-4215, 3728-4215, 3729-4215, 3730-4214, 3735-4214, 3737-4112, 3748-4213, 3752-4575, 3755-4025, 3766-4216, 3770-4382, 3771-4382, 3774-4215, 3776-4192, 3781-4216, 3782-4215, 3784-4215, 3786-4023, 3786-4216, 3791-4211, 3795-4211, 3796-4215, 3796-4216, 3805-4090, 3805-4164, 3807-4164, 3808-4215, 3809-4197, 3810-4144, 3817-4215, 3821-4112, 3821-4152, 3833-4162, 3835-4084, 3843-4103, 3850-4145, 3852-4205, 3852-4215, 3854-4442, 3858-4165, 3863-4121, 3876-4442, 3884-4139, 3885-4382, 3888-4216, 3905-4380, 3941-4382, 3947-4215, 4013-4562, 4081-4243, 4171-4645, 4178-4610, 4194-4692, 4194-4697, 4194-4698, 4194-4699, 4194-4749, 4194-4780, 4194-4904, 4194-4933, 4207-4496, 4208-4470, 4208-4486, 4208-4492, 4208-4493, 4208-4496, 4208-4525, 4208-4644, 4208-4680, 4208-4683, 4208-4687, 4208-4691, 4208-4694, 4208-4702, 4208-4707, 4210-4526, 4211-4496, 4211-4680, 4215-4496, 4216-4496, 4217-4480, 4222-4496, 4241-4382, 4241-4496, 4243-4629, 4252-4612, 4257-4522, 4257-4534, 4257-4541, 4257-4542, 4257-4545, 4257-4562, 4291-4707, 4292-4575, 4298-4605, 4298-4771, 4304-4549, 4304-4659, 4304-4837, 4310-4709, 4310-4711, 4323-4580, 4342-5179, 4363-4639, 4363-5016, 4364-4642, 4364-4916, 4383-4647, 4399-4664, 4410-4663, 4410-4670, 4422-4681, 4429-4677, 4439-4715, 4442-5010, 4452-4699, 4453-5005, 4454-5025, 4484-5200, 4495-4669, 4495-4686, 4495-4691, 4495-4696, 4495-4697, 4496-4762, 4500-5187, 4502-5200, 4510-4749, 4511-4768, 4517-5200, 4521-5200, 4530-5185, 4537-5200, 4551-5183, 4575-4860, 4588-4844, 4591-4866, 4598-5157, 4605-5200, 4619-5197, 4626-5200, 4637-4904, 4647-5200, 4666-5190, 4679-5191, 4682-5200, 4701-5200, 4703-4958, 4707-4961, 4716-4959, 4716-4999, 4719-4946, 4725-4965, 4732-4999, 4736-5021, 4738-4989, 4753-5200, 4757-5013, 4758-5200, 4780-5200, 4794-5200, 4797-5200, 4799-5192, 4806-5135, 4808-5108, 4815-4988, 4819-5088, 4842-5200, 4844-5200, 4848-5200, 4853-5200, 4854-5200, 4858-5200, 4859-5200, 4893-5200, 4904-5200, 4909-5200, 4928-5200, 4945-5200, 4946-5200, 4950-5200, 4956-5200, 4971-5200, 4972-5200, 4973-5200, 4976-5200, 4979-5200, 4980-5178, 4980-5199, 4980-5200, 4984-5200, 4985-5200, 4986-5200, 4989-5200, 4994-5200, 4996-5200, 4998-5200, 5007-5200, 5008-5200, 5010-5200, 5011-5200, 5017-5200, 5028-5200, 5033-5200, 5034-5200, 5046-5200, 5053-5200, 5055-5200, 5093-5200, 5154-5200 22/4622229CB1/ 1-300, 1-484, 24-275, 101-700, 299-820, 301-964, 315-925, 414-1033, 419-994, 516-1036, 612-884, 764-1443, 792-1443, 4330 978-1595, 992-1545, 999-1687, 1037-1301, 1192-1430, 1216-1495, 1222-1799, 1279-1779, 1357-1615, 1428-1746, 1429-1793, 1464-1655, 1464-1684, 1495-1880, 1529-2265, 1575-2005, 1629-2219, 1678-1992, 1714-2170, 1744-2317, 1819-1946, 1912-2384, 1933-2610, 1940-2459, 1960-2540, 1968-2426, 2009-2522, 2055-2660, 2100-2591, 2116-2640, 2131-2638, 2138-2479, 2149-2475, 2152-2750, 2153-2822, 2157-2700, 2191-2517, 2285-2439, 2301-2559, 2306-2520, 2307-2542, 2378-2872, 2411-2699, 2443-2997, 2533-3044, 2546-2787, 2546-3136, 2689-2945, 2709-2985, 2733-3001, 2734-2972, 2734-3009, 2843-3050, 2918-3155, 2918-3182, 2918-3201, 2918-3214, 2918-3218, 2930-3512, 2937-3238, 2997-3246, 3003-3135, 3004-3532, 3019-3269, 3046-3295, 3058-3348, 3107-3358, 3114-3383, 3148-3416, 3236-3489, 3251-3489, 3251-3682, 3251-3802, 3275-3534, 3276-3517, 3282-3554, 3282-3557, 3294-3562, 3319-3572, 3340-3600, 3376-3644, 3387-3675, 3424-3662, 3450-3715, 3505-3728, 3524-3759, 3542-3825, 3552-4117, 3580-4260, 3590-4105, 3605-3731, 3607-3859, 3625-4321, 3634-4156, 3645-3871, 3645-4133, 3672-4313, 3677-4295, 3678-3918, 3684-3945, 3684-4124, 3694-4321, 3709-4317, 3715-4290, 3718-4311, 3733-4151, 3755-3919, 3786-4041, 3786-4044, 3786-4064, 3786-4255, 3786-4313, 3787-4076, 3791-4317, 3811-4329, 3814-4214, 3838-4082, 3839-4051, 3848-4100, 3848-4329, 3852-4315, 3853-4330, 3861-4328, 3877-4133, 3877-4134, 3877-4141, 3877-4330, 3879-4230, 3883-4329, 3885-4300, 3885-4329, 3886-4132, 3887-4329, 3888-4330, 3889-4328, 3890-4271, 3890-4329, 3898-4316, 3899-4330, 3901-4329, 3903-4321, 3903-4328, 3906-4329, 3907-4330, 3909-4330, 3910-4329, 3913-4330, 3914-4324, 3916-4247, 3916-4300, 3916-4328, 3916-4330, 3923-4329, 3923-4330, 3936-4051, 3936-4327, 3936-4330, 3940-4328, 3944-4329, 3965-4328, 3967-4203, 3990-4329, 3998-4329, 3999-4329, 4001-4329, 4010-4230, 4013-4330, 4026-4230, 4027-4230, 4027-4330, 4028-4328, 4030-4230, 4031-4230, 4031-4330, 4052-4229, 4052-4230, 4053-4328, 4053-4330, 4056-4329, 4061-4327, 4062-4329, 4066-4218, 4067-4329, 4068-4279, 4069-4330, 4082-4197, 4099-4328, 4099-4329, 4100-4330, 4109-4249, 4113-4329, 4156-4328 23/72358203CB1/ 1-557, 1-886, 238-885, 550-724, 718-1202, 726-885, 726-886, 736-1198, 774-885, 774-1041, 774-1145, 774-1200, 905-1196, 2851 927-1169, 928-1431, 931-1516, 942-1251, 942-1347, 949-1235, 980-1452, 997-1452, 1002-1259, 1021-1312, 1038-1324, 1042-1522, 1049-1452, 1073-1452, 1085-1259, 1114-1319, 1114-1659, 1142-1259, 1157-1259, 1158-1259, 1174-1259, 1190-1463, 1190-1647, 1210-1295, 1238-1531, 1250-1496, 1259-1428, 1259-1457, 1259-1483, 1259-1538, 1261-1538, 1275-1573, 1290-1896, 1292-1587, 1372-1853, 1437-1689, 1440-1699, 1445-2001, 1446-1717, 1456-1483, 1456-1576, 1456-1603, 1461-1483, 1470-1719, 1470-2068, 1472-1673, 1472-2034, 1478-1711, 1512-1797, 1530-1661, 1533-1736, 1544-1786, 1575-1603, 1609-1898, 1669-2000, 1712-1983, 1732-1877, 1774-1894, 1793-1981, 1793-2297, 1838-2104, 1840-2189, 1843-2639, 1852-2120, 1869-2773, 1888-2221, 1890-2496, 1892-2624, 1904-2510, 1909-2108, 1909-2133, 1911-2454, 1929-2096, 1929-2544, 1941-2198, 1941-2624, 1942-2226, 1943-2214, 1945-2632, 1961-2628, 1966-2208, 1971-2227, 1975-2058, 1984-2068, 1987-2319, 1997-2287, 1997-2291, 1999-2469, 2002-2577, 2004-2799, 2032-2673, 2053-2544, 2063-2239, 2075-2109, 2110-2605, 2111-2639, 2117-2687, 2131-2751, 2132-2808, 2140-2481, 2144-2741, 2146-2695, 2156-2359, 2176-2469, 2184-2816, 2188-2687, 2201-2453, 2202-2815, 2205-2683, 2208-2682, 2209-2764, 2211-2834, 2215-2575, 2215-2771, 2227-2784, 2228-2795, 2228-2844, 2229-2626, 2231-2551, 2232-2632, 2245-2499, 2250-2814, 2272-2725, 2272-2757, 2275-2829, 2282-2532, 2282-2580, 2282-2738, 2282-2815, 2282-2839, 2283-2587, 2295-2742, 2305-2562, 2305-2669, 2310-2552, 2315-2704, 2319-2550, 2324-2565, 2331-2824, 2337-2851, 2354-2601, 2355-2533, 2356-2851, 2360-2779, 2368-2824, 2372-2826, 2373-2824, 2374-2822, 2375-2684, 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2937-3675, 2937-3699, 2947-3625, 2968-3645, 2990-3796, 2998-3725, 3010-3612, 3015-3648, 3023-3708, 3030-3516, 3031-3669, 3070-3653, 3083-3684, 3090-3797, 3136-3695, 3141-3768, 3165-3655, 3185-3727, 3187-4006, 3204-3852, 3204-3861, 3204-3877, 3204-3887, 3210-3861, 3212-3890, 3213-3856, 3220-3899, 3222-3695, 3226-3984, 3227-3889, 3256-3794, 3260-3715, 3265-4018, 3269-3986, 3274-3987, 3277-3817, 3277-3877, 3285-3878, 3304-3996, 3306-4011, 3316-3855, 3320-3914, 3334-3898, 3340-3900, 3343-3911, 3346-3727, 3348-4071, 3349-3995, 3367-3896, 3391-3916, 3393-3990, 3400-4086, 3425-3958, 3441-3947, 3479-4168, 3489-3990, 3494-4035, 3497-4105, 3504-4086, 3504-4096, 3515-4172, 3516-4172, 3517-3797, 3537-4145, 3539-4255, 3540-3943, 3540-3984, 3542-4171, 3542-4172, 3549-4348, 3562-4019, 3565-4153, 3583-4352, 3585-4122, 3585-4150, 3648-3995, 3653-4413, 3657-3981, 3667-4383, 3668-4327, 3677-4182, 3678-3995, 3711-4087, 3732-4286, 3738-4414, 3739-4354, 3740-4377, 3746-4398, 3746-4415, 3750-4392, 3776-3842, 3779-4415, 3808-4415, 3856-4415, 3863-4415, 3865-4415, 3895-4415, 3908-4415, 3917-4415, 3925-4415, 3972-4415 38/7476595CB1/ 1-829, 191-944, 191-950, 191-959, 191-964, 191-971, 192-488, 193-488, 223-488, 234-999, 244-488, 319-999, 398-999, 6306 683-1074, 796-961, 796-1063, 961-6306, 962-1186, 1064-1186, 1064-1299, 1187-1299 39/71824382CB1/ 1-525, 1-532, 188-467, 221-432, 266-533, 403-563, 435-718, 501-740, 585-1133, 594-876, 758-1034, 791-1005, 793-1247, 7151 799-1047, 809-1248, 899-1172, 947-1206, 1077-1708, 1097-1737, 1172-1542, 1172-1583, 1260-1448, 1260-1748, 1283-1763, 1289-1744, 1309-1751, 1320-1744, 1341-1742, 1346-1706, 1385-1749, 1428-2103, 1457-1763, 1511-2109, 1530-2109, 1595-2109, 1612-1752, 1655-2102, 1655-2109, 1739-2109, 1924-2368, 1941-2109, 1946-2109, 1974-2526, 1979-2366, 1979-2642, 1980-2534, 2039-2274, 2039-2319, 2039-2536, 2039-2644, 2043-2109, 2148-2316, 2148-2335, 2148-2484, 2148-2542, 2148-2579, 2148-2588, 2148-2649, 2148-2753, 2148-2757, 2151-2757, 2156-2306, 2168-2413, 2202-2278, 2242-2889, 2243-2917, 2253-2609, 2284-2829, 2288-2829, 2326-2589, 2326-2934, 2326-2959, 2326-2975, 2388-3083, 2398-2526, 2445-2757, 2447-2757, 2503-3181, 2576-3079, 2581-2757, 2630-2740, 2634-3079, 2658-3181, 2704-2909, 2977-3181, 3102-3691, 3102-3769, 3104-3769, 3126-3181, 3333-3941, 3415-3943, 3452-3911, 3616-3912, 3616-4100, 3634-4171, 3634-4205, 3693-4292, 3890-4478, 3976-4399, 3976-4654, 4023-4452, 4090-4498, 4156-4417, 4202-4705, 4254-4915, 4254-4945, 4303-4705, 4431-4984, 4513-5252, 4548-5253, 4613-4854, 4822-5203, 4885-5133, 4901-5173, 4901-5554, 4905-5581, 4968-5531, 4980-5438, 5006-5562, 5022-5182, 5028-5697, 5044-5663, 5061-5737, 5063-5562, 5064-5562, 5125-5430, 5154-5300, 5225-5505, 5293-5602, 5332-5781, 5335-5590, 5397-5697, 5409-5913, 5453-5715, 5507-5701, 5518-6120, 5569-6181, 5647-6231, 5667-6078, 5716-5948, 5806-6163, 5906-6157, 5906-6536, 6047-6292, 6147-6420, 6175-6590, 6176-6467, 6238-6447, 6238-7024, 6254-6429, 6269-6560, 6284-6600, 6397-6655, 6397-6973, 6423-7036, 6471-6717, 6497-7118, 6497-7125, 6521-7122, 6629-7087, 6643-6908, 6657-7116, 6820-7062, 6820-7124, 6820-7151, 6829-7077, 6838-7069, 6901-7136 40/3566882CB1/ 1-219, 54-238, 54-571, 517-1197, 517-1241, 695-1241, 757-2216, 1241-1477, 1241-1534, 1241-1706, 1241-1779, 1241-1810, 2378 1241-1812, 1241-1835, 1241-1846, 1241-1864, 1241-1873, 1242-1794, 1347-2004, 1372-1910, 1376-1881, 1488-1808, 1519-2155, 1542-2088, 1573-2221, 1576-2112, 1615-2026, 1618-2182, 1624-2139, 1641-2155, 1645-2316, 1652-2139, 1711-2218, 1717-1968, 1767-2370, 1785-2378, 1826-2367, 1844-2258, 1928-2143, 2032-2202, 2036-2206, 2304-2361

[0377] TABLE 5 Polynucleotide Incyte Representative SEQ ID NO: Project ID: Library 21 4615110CB1 BRAYDIN03 22 4622229CB1 BRAINON01 23 72358203CB1 BRAITUT03 24 4885040CB1 ENDANOT01 25 7484507CB1 BRAIFEN08 26 7198931CB1 SYNORAB01 27 7482905CB1 BMARTXE01 28 7483019CB1 BMARTXT02 29 5455490CB1 HNT2AGT01 30 5547067CB1 BRAIFEE05 31 71675660CB1 TESTNOT17 32 71678683CB1 TESTNOT17 33 7474567CB1 UCMCNOT02 34 3838946CB1 NOSEDIN01 35 72001176CB1 THP1NOT03 36 55064363CB1 BRAIFET02 37 7482044CB1 BRAUNOR01 39 71824382CB1 BRABDIR01 40 3566882CB1 LUNLTUE02

[0378] TABLE 6 Library Vector Library Description BMARTXE01 pINCY This 5′ biased random primed library was constructed using RNA isolated from treated SH-SY5Y cells derived from a metastatic bone marrow neuroblastoma, removed from a 4-year-old Caucasian female (Schering AG). The medium was MEM/HAM'S F12 with 10% fetal calf serum. After reaching about 80% confluency cells were treated with 6-Hydroxydopamine (6-OHDA) at 100 microM for 8 hours. BMARTXT02 pINCY Library was constructed using RNA isolated from treated SH-SY5Y cell line derived from bone marrow neuroblastoma tumor cells removed from a 4-year-old Caucasian female. The cells were cultured in the presence of retinoic acid. BRABDIR01 pINCY Library was constructed using RNA isolated from diseased cerebellum tissue removed from the brain of a 57-year-old Caucasian male, who died from a cerebrovascular accident. Patient history included Huntington's disease, emphysema, and tobacco abuse. BRAIFEE05 PCDNA2.1 This 5′ biased random primed library was constructed using RNA isolated from brain tissue removed from a Caucasian male fetus who was stillborn with a hypoplastic left heart at 23 weeks' gestation. BRAIFEN08 pINCY This normalized fetal brain tissue library was constructed from 400 thousand independent clones from a fetal brain tissue library. Starting RNA was made from brain tissue removed from a Caucasian male fetus who was stillborn with a hypoplastic left heart at 23 weeks' gestation. The library was normalized in 2 rounds using conditions adapted from Soares et al., PNAS (1994) 91: 9228 and Bonaldo et al., Genome Research (1996) 6: 791, except that a significantly longer (48 hours/round) reannealing hybridization was used. BRAIFET02 pINCY Library was constructed using RNA isolated from brain tissue removed from a Caucasian male fetus, who was stillborn with a hypoplastic left heart at 23 weeks' gestation. BRAINON01 PSPORT1 Library was constructed and normalized from 4.88 million independent clones from the BRAINOT03 library. RNA was made from brain tissue removed from a 26-year-old Caucasian male during cranioplasty and excision of a cerebral meningeal lesion. Pathology for the associated tumor tissue indicated a grade 4 oligoastrocytoma in the right fronto-parietal part of the brain. BRAITUT03 PSPORT1 Library was constructed using RNA isolated from brain tumor tissue removed from the left frontal lobe of a 17-year-old Caucasian female during excision of a cerebral meningeal lesion. Pathology indicated a grade 4 fibrillary giant and small-cell astrocytoma. Family history included benign hypertension and cerebrovascular disease. BRAUNOR01 pINCY This random primed library was constructed using RNA isolated from striatum, globus pallidus and posterior putamen tissue removed from an 81-year-old Caucasian female who died from a hemorrhage and ruptured thoracic aorta due to atherosclerosis. Pathology indicated moderate atherosclerosis involving the internal carotids, bilaterally; microscopic infarcts of the frontal cortex and hippocampus; and scattered diffuse amyloid plaques and neurofibrillary tangles, consistent with age. Grossly, the leptomeninges showed only mild thickening and hyalinization along the superior sagittal sinus. The remainder of the leptomeninges was thin and contained some congested blood vessels. Mild atrophy was found mostly in the frontal poles and lobes, and temporal lobes, bilaterally. Microscopically, there were pairs of Alzheimer type II astrocytes within the deep layers of the neocortex. There was increased satellitosis around neurons in the deep gray matter in the middle frontal cortex. The amygdala contained rare diffuse plaques and neurofibrillary tangles. The posterior hippocampus contained a microscopic area of cystic cavitation with hemosiderin laden macrophages surrounded by reactive gliosis. Patient history included sepsis, cholangitis, post-operative atelectasis, pneumonia CAD, cardiomegaly due to left ventricular hypertrophy, splenomegaly, arteriolonephrosclerosis, nodular colloidal goiter, emphysema, CHF, hypothyroidism, and peripheral vascular disease. BRAYDIN03 pINCY This normalized library was constructed from 6.7 million independent clones from a brain tissue library. Starting RNA was made from RNA isolated from diseased hypothalamus tissue removed from a 57-year-old Caucasian male who died from a cerebrovascular accident. Patient history included Huntington's disease and emphysema. The library was normalized in 2 rounds using conditions adapted from Soares et al., PNAS (1994) 91: 9228 and Bonaldo et al., Genome Research (1996) 6: 791, except that a significantly longer (48-hours/round) reannealing hybridization was used. The library was linearized and recircularized to select for insert containing clones. ENDANOT01 PBLUESCRIPT Library was constructed using RNA isolated from aortic endothelial cell tissue from an explanted heart removed from a male during a heart transplant. HNT2AGT01 PBLUESCRIPT Library was constructed at Stratagene (STR937233), using RNA isolated from the hNT2 cell line derived from a human teratocarcinoma that exhibited properties characteristic of a committed neuronal precursor. Cells were treated with retinoic acid for 5 weeks and with mitotic inhibitors for two weeks and allowed to mature for an additional 4 weeks in conditioned medium. LUNLTUE02 PCDNA2.1 This 5′ biased random primed library was constructed using RNA isolated from left upper lobe lung tumor tissue removed from a 56-year-old Caucasian male during complete pneumonectomy, pericardectomy and regional lymph node excision. Pathology indicated grade 3 squamous cell carcinoma forming a mass in the left upper lobe centrally. The tumor extended through pleura into adjacent pericardium. Patient history included hemoptysis and tobacco abuse. Family history included benign hypertension, cerebrovascular accident, atherosclerotic coronary artery disease in the mother; prostate cancer in the father; and type II diabetes in the sibling(s). NOSEDIN01 pINCY This normalized nasal polyp tissue library was constructed from 1.08 million independent clones from a pooled nasal polyp tissue library. Starting RNA was made from pooled cDNA from two donors. cDNA was generated using mRNA isolated from a nasal polyp removed from a 78-year-old Caucasian male during nasal polypectomy (donor A) and from nasal polyps from another donor (donor B). Pathology (A) indicated a nasal polyp and striking eosinophilia, especially deep in the epithelium. In many instances, eosinophils were undergoing frank necrosis with striking deposition of Charcot-Leyden crystals. Foci of eosinophil infiltration in small islands of cells were seen in certain areas, and those areas closer to the appearance surface were losing definition and evidently undergoing necrosis. Examination of respiratory epithelium showed loss of surface epithelium in many areas, and there was a tendency for cells to aggregate around the epithelium. This nasal polyp showed typical histology for polypoid change associated with allergic disease. Patient history included asthma, allergy tests (which were positive for histamine but negative for common substances), a pulmonary function test (PFT, which showed reduction in the forced expiratory volume (FEV), with increase after use of a bronchodilator), and nasal polyps. Patient history (A) included asthma. Previous surgery (A) included a nasal polypectomy. The patient was not using glucocorticoids in treatment for asthma. The library was normalized in 1 round using conditions adapted from Soares et al., PNAS (1994) 91: 9228-9232 and Bonaldo et al., Genome Research 6 (1996): 791, except that a significantly longer (48 hours/round) reannealing hybridization was used. SYNORAB01 PBLUESCRIPT Library was constructed using RNA isolated from the synovial membrane tissue of a 68-year-old Caucasian female with rheumatoid arthritis. TESTNOT17 pINCY Library was constructed from testis tissue removed from a 26-year-old Caucasian male who died from head trauma due to a motor vehicle accident. Serologies were negative. Patient history included a hernia at birth, tobacco use (1 1/2 ppd), marijuana use, and daily alcohol use (beer and hard liquor). THP1NOT03 pINCY Library was constructed using RNA isolated from untreated THP-1 cells. THP-1 is a human promonocyte line derived from the peripheral blood of a 1-year-old Caucasian male with acute monocytic leukemia (ref. int. j. Cancer (1980) 26: 171) UCMCNOT02 pINCY Library was constructed using RNA isolated from mononuclear cells obtained from the umbilical cord blood of nine individuals.

[0379] TABLE 7 Program Description Reference Parameter Threshold ABI A program that removes vector sequences and Applied Biosystems, Foster City, CA. FACTURA masks ambiguous bases in nucleic acid sequences. ABI/ A Fast Data Finder useful in comparing and Applied Biosystems, Foster City, CA; Mismatch < 50% PARACEL annotating amino acid or nucleic acid sequences. Paracel Inc., Pasadena, CA. FDF ABI Auto- A program that assembles nucleic acid sequences. Applied Biosystems, Foster City, CA. Assembler BLAST A Basic Local Alignment Search Tool useful in Altschul, S. F. et al. (1990) J. Mol. Biol. ESTs: Probability value = sequence similarity search for amino acid and 215: 403-410; Altschul, S. F. et al. (1997) 1.0E−8 or less nucleic acid sequences. BLAST includes five Nucleic Acids Res. 25: 3389-3402. Full Length sequences: functions: blastp, blastn, blastx, tblastn, and tblastx. Probability value = 1.0E−10 or less FASTA A Pearson and Lipman algorithm that searches for Pearson, W. R. and D. J. Lipman (1988) Proc. ESTs: fasta E value = similarity between a query sequence and a group of Natl. Acad Sci. USA 85: 2444-2448; Pearson, 1.06E−6 Assembled ESTs: sequences of the same type. FASTA comprises as W. R. (1990) Methods Enzymol. 183: 63-98; fasta Identity = 95% or least five functions: fasta, tfasta, fastx, tfastx, and and Smith, T. F. and M. S. Waterman (1981) greater and Match length = ssearch. Adv. Appl. Math. 2: 482-489. 200 bases or greater; fastx E value = 1.0E−8 or less Full Length sequences: fastx score = 100 or greater BLIMPS A BLocks IMProved Searcher that matches a Henikoff, S. and J. G. Henikoff (1991) Nucleic Probability value = 1.0E−3 sequence against those in BLOCKS, PRINTS, Acids Res. 19: 6565-6572; Henikoff, J. G. and or less DOMO, PRODOM, and PFAM databases to search S. Henikoff (1996) Methods Enzymol. for gene families, sequence homology, and 266: 88-105; and Attwood, T. K. et al. (1997) structural fingerprint regions. J. Chem. Inf. Comput. Sci. 37: 417-424. HMMER An algorithm for searching a query sequence against Krogh, A. et al. (1994) J. Mol. Biol. PFAM hits: Probability hidden Markov model (HMM)-based databases of 235: 1501-1531; Sonnhammer, E. L. L. et al. value = 1.0E−3 or less protein family consensus sequences, such as PFAM. (1988) Nucleic Acids Res. 26: 320-322; Signal peptide hits: Score = 0 Durbin, R. et al. (1998) Our World View, in a or greater Nutshell, Cambridge Univ. Press, pp. 1-350. ProfileScan An algorithm that searches for structural and sequence Gribskov, M. et al. (1988) CABIOS 4: 61-66; Normalized quality score ≧ motifs in protein sequences that match sequence patterns Gribskov, M. et al. (1989) Methods Enzymol. GCG-specified “HIGH” value defined in Prosite. 183: 146-159; Bairoch, A. et al. (1997) for that particular Prosite Nucleic Acids Res. 25: 217-221. motif. Generally, score = 1.4-2.1. Phred A base-calling algorithm that examines automated Ewing, B. et al. (1998) Genome Res. sequencer traces with high sensitivity and probability. 8: 175-185; Ewing, B. and P. Green (1998) Genome Res. 8: 186-194. Phrap A Phils Revised Assembly Program including SWAT and Smith, T. F. and M. S. Waterman (1981) Adv. Score = 120 or greater; CrossMatch, programs based on efficient implementation Appl. Math. 2: 482-489; Smith, T. F. and M. Match length = 56 or greater of the Smith-Waterman algorithm, useful in searching S. Waterman (1981) J. Mol. Biol. 147: 195- sequence homology and assembling DNA sequences. 197; and Green, P., University of Washington, Seattle, WA. Consed A graphical tool for viewing and editing Phrap Gordon, D. et al. (1998) Genome Res. 8: assemblies. 195-202. SPScan A weight matrix analysis program that scans protein Nielson, H. et al. (1997) Protein Engineering Score = 3.5 or greater sequences for the presence of secretory signal peptides. 10: 1-6; Claverie, J. M. and S. Audic (1997) CABIOS 12: 431-439. TMAP A program that uses weight matrices to delineate Persson, B. and P. Argos (1994) J. Mol. Biol. transmembrane segments on protein sequences and 237: 182-192; Persson, B. and P. Argos (1996) determine orientation. Protein Sci. 5: 363-371. TMHMMER A program that uses a hidden Markov model (HMM) to Sonnhammer, E. L. et al. (1998) Proc. Sixth delineate transmembrane segments on protein sequences Intl. Conf. on Intelligent Systems for Mol. and determine orientation. Biol., Glasgow et al., eds., The Am. Assoc. for Artificial Intelligence Press, Menlo Park, CA, pp. 175-182. Motifs A program that searches amino acid sequences for Bairoch, A. et al. (1997) Nucleic Acids Res. patterns that matched those defined in Prosite. 25: 217-221; Wisconsin Package Program Manual, version 9, page M51-59, Genetics Computer Group, Madison, WI.

[0380]

1 40 1 1636 PRT Homo sapiens misc_feature Incyte ID No 4615110CD1 1 Met Glu Ala Val Pro Arg Met Pro Met Ile Trp Leu Asp Leu Lys 1 5 10 15 Glu Ala Gly Asp Phe His Phe Gln Pro Ala Val Lys Lys Phe Val 20 25 30 Leu Lys Asn Tyr Gly Glu Asn Pro Glu Ala Tyr Asn Glu Glu Leu 35 40 45 Lys Lys Leu Glu Leu Leu Arg Gln Asn Ala Val Arg Val Pro Arg 50 55 60 Asp Phe Glu Gly Cys Ser Val Leu Arg Lys Tyr Leu Gly Gln Leu 65 70 75 His Tyr Leu Gln Ser Arg Val Pro Met Gly Ser Gly Gln Glu Ala 80 85 90 Ala Val Pro Val Thr Trp Thr Glu Ile Phe Ser Gly Lys Ser Val 95 100 105 Ala His Glu Asp Ile Lys Tyr Glu Gln Ala Cys Ile Leu Tyr Asn 110 115 120 Leu Gly Ala Leu His Ser Met Leu Gly Ala Met Asp Lys Arg Val 125 130 135 Ser Glu Glu Gly Met Lys Val Ser Cys Thr His Phe Gln Cys Ala 140 145 150 Ala Gly Ala Phe Ala Tyr Leu Arg Glu His Phe Pro Gln Ala Tyr 155 160 165 Ser Val Asp Met Ser Arg Gln Ile Leu Thr Leu Asn Val Asn Leu 170 175 180 Met Leu Gly Gln Ala Gln Glu Cys Leu Leu Glu Lys Ser Met Leu 185 190 195 Asp Asn Arg Lys Ser Phe Leu Val Ala Arg Ile Ser Ala Gln Val 200 205 210 Val Asp Tyr Tyr Lys Glu Ala Cys Arg Ala Leu Glu Asn Pro Asp 215 220 225 Thr Ala Ser Leu Leu Gly Arg Ile Gln Lys Asp Trp Lys Lys Leu 230 235 240 Val Gln Met Lys Ile Tyr Tyr Phe Ala Ala Val Ala His Leu His 245 250 255 Met Gly Lys Gln Ala Glu Glu Gln Gln Lys Phe Gly Glu Arg Val 260 265 270 Ala Tyr Phe Gln Ser Ala Leu Asp Lys Leu Asn Glu Ala Ile Lys 275 280 285 Leu Ala Lys Gly Gln Pro Asp Thr Val Gln Asp Ala Leu Arg Phe 290 295 300 Thr Met Asp Val Ile Gly Gly Lys Tyr Asn Ser Ala Lys Lys Asp 305 310 315 Asn Asp Phe Ile Tyr His Glu Ala Val Pro Ala Leu Asp Thr Leu 320 325 330 Gln Pro Val Lys Gly Ala Pro Leu Val Lys Pro Leu Pro Val Asn 335 340 345 Pro Thr Asp Pro Ala Val Thr Gly Pro Asp Ile Phe Ala Lys Leu 350 355 360 Val Pro Met Ala Ala His Glu Ala Ser Ser Leu Tyr Ser Glu Glu 365 370 375 Lys Ala Lys Leu Leu Arg Glu Met Met Ala Lys Ile Glu Asp Lys 380 385 390 Asn Glu Val Leu Asp Gln Phe Met Asp Ser Met Gln Leu Asp Pro 395 400 405 Glu Thr Val Asp Asn Leu Asp Ala Tyr Ser His Ile Pro Pro Gln 410 415 420 Leu Met Glu Lys Cys Ala Ala Leu Ser Val Arg Pro Asp Thr Val 425 430 435 Arg Asn Leu Val Gln Ser Met Gln Val Leu Ser Gly Val Phe Thr 440 445 450 Asp Val Glu Ala Ser Leu Lys Asp Ile Arg Asp Leu Leu Glu Glu 455 460 465 Asp Glu Leu Leu Glu Gln Lys Phe Gln Glu Ala Val Gly Gln Ala 470 475 480 Gly Ala Ile Ser Ile Thr Ser Lys Ala Glu Leu Ala Glu Val Arg 485 490 495 Arg Glu Trp Ala Lys Tyr Met Glu Val His Glu Lys Ala Ser Phe 500 505 510 Thr Asn Ser Glu Leu His Arg Ala Met Asn Leu His Val Gly Asn 515 520 525 Leu Arg Leu Leu Ser Gly Pro Leu Asp Gln Val Arg Ala Ala Leu 530 535 540 Pro Thr Pro Ala Leu Ser Pro Glu Asp Lys Ala Val Leu Gln Asn 545 550 555 Leu Lys Arg Ile Leu Ala Lys Val Gln Glu Met Arg Asp Gln Arg 560 565 570 Val Ser Leu Glu Gln Gln Leu Arg Glu Leu Ile Gln Lys Asp Asp 575 580 585 Ile Thr Ala Ser Leu Val Thr Thr Asp His Ser Glu Met Lys Lys 590 595 600 Leu Phe Glu Glu Gln Leu Lys Lys Tyr Asp Gln Leu Lys Val Tyr 605 610 615 Leu Glu Gln Asn Leu Ala Ala Gln Asp Arg Val Leu Cys Ala Leu 620 625 630 Thr Glu Ala Asn Val Gln Tyr Ala Ala Val Arg Arg Val Leu Ser 635 640 645 Asp Leu Asp Gln Lys Trp Asn Ser Thr Leu Gln Thr Leu Val Ala 650 655 660 Ser Tyr Glu Ala Tyr Glu Asp Leu Met Lys Lys Ser Gln Glu Gly 665 670 675 Arg Asp Phe Tyr Ala Asp Leu Glu Ser Lys Val Ala Ala Leu Leu 680 685 690 Glu Arg Thr Gln Ser Thr Cys Gln Ala Arg Glu Ala Ala Arg Gln 695 700 705 Gln Leu Leu Asp Arg Glu Leu Lys Lys Lys Pro Pro Pro Arg Pro 710 715 720 Thr Ala Pro Lys Pro Leu Leu Pro Arg Arg Glu Glu Ser Glu Ala 725 730 735 Val Glu Ala Gly Asp Pro Pro Glu Glu Leu Arg Ser Leu Pro Pro 740 745 750 Asp Met Val Ala Gly Pro Arg Leu Pro Asp Thr Phe Leu Gly Ser 755 760 765 Ala Thr Pro Leu His Phe Pro Pro Ser Pro Phe Pro Ser Ser Thr 770 775 780 Gly Pro Gly Pro His Tyr Leu Ser Gly Pro Leu Pro Pro Gly Thr 785 790 795 Tyr Ser Gly Pro Thr Gln Leu Ile Gln Pro Arg Ala Pro Gly Pro 800 805 810 His Ala Met Pro Val Ala Pro Gly Pro Ala Leu Tyr Pro Ala Pro 815 820 825 Ala Tyr Thr Pro Glu Leu Gly Leu Val Pro Arg Ser Ser Pro Gln 830 835 840 His Gly Val Val Ser Ser Pro Tyr Val Gly Val Gly Pro Ala Pro 845 850 855 Pro Val Ala Gly Leu Pro Ser Ala Pro Pro Pro Gln Phe Ser Gly 860 865 870 Pro Glu Leu Ala Met Ala Val Arg Pro Ala Thr Thr Thr Val Asp 875 880 885 Ser Ile Gln Ala Pro Ile Pro Ser His Thr Ala Pro Arg Pro Asn 890 895 900 Pro Thr Pro Ala Pro Pro Pro Pro Cys Phe Pro Val Pro Pro Pro 905 910 915 Gln Pro Leu Pro Thr Pro Tyr Thr Tyr Pro Ala Gly Ala Lys Gln 920 925 930 Pro Ile Pro Ala Gln His His Phe Ser Ser Gly Ile Pro Thr Gly 935 940 945 Phe Pro Ala Pro Arg Ile Gly Pro Gln Pro Gln Pro His Pro Gln 950 955 960 Pro His Pro Ser Gln Ala Phe Gly Pro Gln Pro Pro Gln Gln Pro 965 970 975 Leu Pro Leu Gln His Pro His Leu Phe Pro Pro Gln Ala Pro Gly 980 985 990 Leu Leu Pro Pro Gln Ser Pro Tyr Pro Tyr Ala Pro Gln Pro Gly 995 1000 1005 Val Leu Gly Gln Pro Pro Pro Pro Leu His Thr Gln Leu Tyr Pro 1010 1015 1020 Gly Pro Ala Gln Asp Pro Leu Pro Ala His Ser Gly Ala Leu Pro 1025 1030 1035 Phe Pro Ser Pro Gly Pro Pro Gln Pro Pro His Pro Pro Leu Ala 1040 1045 1050 Tyr Gly Pro Ala Pro Ser Thr Arg Pro Met Gly Pro Gln Ala Ala 1055 1060 1065 Pro Leu Thr Ile Arg Gly Pro Ser Ser Ala Gly Gln Ser Thr Pro 1070 1075 1080 Ser Pro His Leu Val Pro Ser Pro Ala Pro Ser Pro Gly Pro Gly 1085 1090 1095 Pro Val Pro Pro Arg Pro Pro Ala Ala Glu Pro Pro Pro Cys Leu 1100 1105 1110 Arg Arg Gly Ala Ala Ala Ala Asp Leu Leu Ser Ser Ser Pro Glu 1115 1120 1125 Ser Gln His Gly Gly Thr Gln Ser Pro Gly Gly Gly Gln Pro Leu 1130 1135 1140 Leu Gln Pro Thr Lys Val Asp Ala Ala Glu Gly Arg Arg Pro Gln 1145 1150 1155 Ala Leu Arg Leu Ile Glu Arg Asp Pro Tyr Glu His Pro Glu Arg 1160 1165 1170 Leu Arg Gln Leu Gln Gln Glu Leu Glu Ala Phe Arg Gly Gln Leu 1175 1180 1185 Gly Asp Val Gly Ala Leu Asp Thr Val Trp Arg Glu Leu Gln Asp 1190 1195 1200 Ala Gln Glu His Asp Ala Arg Gly Arg Ser Ile Ala Ile Ala Arg 1205 1210 1215 Cys Tyr Ser Leu Lys Asn Arg His Gln Asp Val Met Pro Tyr Asp 1220 1225 1230 Ser Asn Arg Val Val Leu Arg Ser Gly Lys Asp Asp Tyr Ile Asn 1235 1240 1245 Ala Ser Cys Val Glu Gly Leu Ser Pro Tyr Cys Pro Pro Leu Val 1250 1255 1260 Ala Thr Gln Ala Pro Leu Pro Gly Thr Ala Ala Asp Phe Trp Leu 1265 1270 1275 Met Val His Glu Gln Lys Val Ser Val Ile Val Met Leu Val Ser 1280 1285 1290 Glu Ala Glu Met Glu Lys Gln Lys Val Ala Arg Tyr Phe Pro Thr 1295 1300 1305 Glu Arg Gly Gln Pro Met Val His Gly Ala Leu Ser Leu Ala Leu 1310 1315 1320 Ser Ser Val Arg Ser Thr Glu Thr His Val Glu Arg Val Leu Ser 1325 1330 1335 Leu Gln Phe Arg Asp Gln Ser Leu Lys Arg Ser Leu Val His Leu 1340 1345 1350 His Phe Pro Thr Trp Pro Glu Leu Gly Leu Pro Asp Ser Pro Ser 1355 1360 1365 Asn Leu Leu Arg Phe Ile Gln Glu Val His Ala His Tyr Leu His 1370 1375 1380 Gln Arg Pro Leu His Thr Pro Ile Ile Val His Cys Ser Ser Gly 1385 1390 1395 Val Gly Arg Thr Gly Ala Phe Ala Leu Leu Tyr Ala Ala Val Gln 1400 1405 1410 Glu Val Glu Ala Gly Asn Gly Ile Pro Glu Leu Pro Gln Leu Val 1415 1420 1425 Arg Arg Met Arg Gln Gln Arg Lys His Met Leu Gln Glu Lys Leu 1430 1435 1440 His Leu Arg Phe Cys Tyr Glu Ala Val Val Arg His Val Glu Gln 1445 1450 1455 Val Leu Gln Arg His Gly Val Pro Pro Pro Cys Lys Pro Leu Ala 1460 1465 1470 Ser Ala Ser Ile Ser Gln Lys Asn His Leu Pro Gln Asp Ser Gln 1475 1480 1485 Asp Leu Val Leu Gly Gly Asp Val Pro Ile Ser Ser Ile Gln Ala 1490 1495 1500 Thr Ile Ala Lys Leu Ser Ile Arg Pro Pro Gly Gly Leu Glu Ser 1505 1510 1515 Pro Val Ala Ser Leu Pro Gly Pro Ala Glu Pro Pro Gly Leu Pro 1520 1525 1530 Pro Ala Ser Leu Pro Glu Ser Thr Pro Ile Pro Ser Ser Ser Pro 1535 1540 1545 Pro Pro Leu Ser Ser Pro Leu Pro Glu Ala Pro Gln Pro Lys Glu 1550 1555 1560 Glu Pro Pro Val Pro Glu Ala Pro Ser Ser Gly Pro Pro Ser Ser 1565 1570 1575 Ser Leu Glu Leu Leu Ala Ser Leu Thr Pro Glu Ala Phe Ser Leu 1580 1585 1590 Asp Ser Ser Leu Arg Gly Lys Gln Arg Met Ser Lys His Asn Phe 1595 1600 1605 Leu Gln Ala His Asn Gly Gln Gly Leu Arg Ala Thr Arg Pro Ser 1610 1615 1620 Asp Asp Pro Leu Ser Leu Leu Asp Pro Leu Trp Thr Leu Asn Lys 1625 1630 1635 Thr 2 673 PRT Homo sapiens misc_feature Incyte ID No 4622229CD1 2 Met Asp Arg Pro Ala Ala Ala Ala Ala Ala Gly Cys Glu Gly Gly 1 5 10 15 Gly Gly Pro Asn Pro Gly Pro Ala Gly Gly Arg Arg Pro Pro Arg 20 25 30 Ala Ala Gly Gly Ala Thr Ala Gly Ser Arg Gln Pro Ser Val Glu 35 40 45 Thr Leu Asp Ser Pro Thr Gly Ser His Val Glu Trp Cys Lys Gln 50 55 60 Leu Ile Ala Ala Thr Ile Ser Ser Gln Ile Ser Gly Ser Val Thr 65 70 75 Ser Glu Asn Val Ser Arg Asp Tyr Lys Val Phe Arg Arg Pro Asp 80 85 90 Leu Arg Ala Leu Arg Asp Gly Asn Lys Leu Ala Gln Met Glu Glu 95 100 105 Ala Pro Leu Phe Pro Gly Glu Ser Ile Lys Ala Ile Val Lys Asp 110 115 120 Val Met Tyr Ile Cys Pro Phe Met Gly Ala Val Ser Gly Thr Leu 125 130 135 Thr Val Thr Asp Phe Lys Leu Tyr Phe Lys Asn Val Glu Arg Asp 140 145 150 Pro His Phe Ile Leu Asp Val Pro Leu Gly Val Ile Ser Arg Val 155 160 165 Glu Lys Ile Gly Ala Gln Ser His Gly Asp Asn Ser Cys Gly Ile 170 175 180 Glu Ile Val Cys Lys Asp Met Arg Asn Leu Arg Leu Ala Tyr Lys 185 190 195 Gln Glu Glu Gln Ser Lys Leu Gly Ile Phe Glu Asn Leu Asn Lys 200 205 210 His Ala Phe Pro Leu Ser Asn Gly Gln Ala Leu Phe Ala Phe Ser 215 220 225 Tyr Lys Glu Lys Phe Pro Ile Asn Gly Trp Lys Val Tyr Asp Pro 230 235 240 Val Ser Glu Tyr Lys Arg Gln Gly Leu Pro Asn Glu Ser Trp Lys 245 250 255 Ile Ser Lys Ile Asn Ser Asn Tyr Glu Phe Cys Asp Thr Tyr Pro 260 265 270 Ala Ile Ile Val Val Pro Thr Ser Val Lys Asp Asp Asp Leu Ser 275 280 285 Lys Val Ala Ala Phe Arg Ala Lys Gly Arg Val Pro Val Leu Ser 290 295 300 Trp Ile His Pro Glu Ser Gln Ala Thr Ile Thr Arg Cys Ser Gln 305 310 315 Pro Leu Val Gly Pro Asn Asp Lys Arg Cys Lys Glu Asp Glu Lys 320 325 330 Tyr Leu Gln Thr Ile Met Asp Ala Asn Ala Gln Ser His Lys Leu 335 340 345 Ile Ile Phe Asp Ala Arg Gln Asn Ser Val Ala Asp Thr Asn Lys 350 355 360 Thr Lys Gly Gly Gly Tyr Glu Ser Glu Ser Ala Tyr Pro Asn Ala 365 370 375 Glu Leu Val Phe Leu Glu Ile His Asn Ile His Val Met Arg Glu 380 385 390 Ser Leu Arg Lys Leu Lys Glu Ile Val Tyr Pro Ser Ile Asp Glu 395 400 405 Ala Arg Trp Leu Ser Asn Val Asp Gly Thr His Trp Leu Glu Tyr 410 415 420 Ile Arg Met Leu Leu Ala Gly Ala Val Arg Ile Ala Asp Lys Ile 425 430 435 Glu Ser Gly Lys Thr Ser Val Val Val His Cys Ser Asp Gly Trp 440 445 450 Asp Arg Thr Ala Gln Leu Thr Ser Leu Ala Met Leu Met Leu Asp 455 460 465 Ser Tyr Tyr Arg Thr Ile Lys Gly Phe Glu Thr Leu Val Glu Lys 470 475 480 Glu Trp Ile Ser Phe Gly His Arg Phe Ala Leu Arg Val Gly His 485 490 495 Gly Asn Asp Asn His Ala Asp Ala Asp Arg Ser Pro Ile Phe Leu 500 505 510 Gln Phe Val Asp Cys Val Trp Gln Met Thr Arg Gln Phe Pro Ser 515 520 525 Ala Phe Glu Phe Asn Glu Leu Phe Leu Ile Thr Ile Leu Asp His 530 535 540 Leu Tyr Ser Cys Leu Phe Gly Thr Phe Leu Cys Asn Cys Glu Gln 545 550 555 Gln Arg Phe Lys Glu Asp Val Tyr Thr Lys Thr Ile Ser Leu Trp 560 565 570 Ser Tyr Ile Asn Ser Gln Leu Asp Glu Phe Ser Asn Pro Phe Phe 575 580 585 Val Asn Tyr Glu Asn His Val Leu Tyr Pro Val Ala Ser Leu Ser 590 595 600 His Leu Glu Leu Trp Val Asn Tyr Tyr Val Arg Trp Asn Pro Arg 605 610 615 Met Arg Pro Gln Met Pro Ile His Gln Asn Leu Lys Glu Leu Leu 620 625 630 Ala Val Arg Ala Glu Leu Gln Lys Arg Val Glu Gly Leu Gln Arg 635 640 645 Glu Val Ala Thr Arg Ala Val Ser Ser Ser Ser Glu Arg Gly Ser 650 655 660 Ser Pro Ser His Ser Ala Thr Ser Val His Thr Ser Val 665 670 3 459 PRT Homo sapiens misc_feature Incyte ID No 72358203CD1 3 Met Ser Ala Gly Trp Phe Arg Arg Arg Phe Leu Pro Gly Glu Pro 1 5 10 15 Leu Pro Ala Pro Arg Pro Pro Gly Pro His Ala Ser Pro Val Pro 20 25 30 Tyr Arg Arg Pro Arg Phe Leu Arg Gly Ser Ser Ser Ser Pro Gly 35 40 45 Ala Ala Asp Ala Ser Arg Arg Pro Asp Ser Arg Pro Val Arg Ser 50 55 60 Pro Ala Arg Gly Arg Thr Leu Pro Trp Asn Ala Gly Tyr Ala Glu 65 70 75 Ile Ile Asn Ala Glu Lys Ser Glu Phe Asn Glu Asp Gln Ala Ala 80 85 90 Cys Gly Lys Leu Cys Ile Arg Arg Cys Glu Phe Gly Ala Glu Glu 95 100 105 Glu Trp Leu Thr Leu Cys Pro Glu Glu Phe Leu Thr Gly His Tyr 110 115 120 Trp Ala Leu Phe Asp Gly His Gly Gly Pro Ala Ala Ala Ile Leu 125 130 135 Ala Ala Asn Thr Leu His Ser Cys Leu Arg Arg Gln Leu Glu Ala 140 145 150 Val Val Glu Gly Leu Val Ala Thr Gln Pro Pro Met His Leu Asn 155 160 165 Gly Arg Cys Ile Cys Pro Ser Asp Pro Gln Phe Val Glu Glu Lys 170 175 180 Gly Ile Arg Ala Glu Asp Leu Val Ile Gly Ala Leu Glu Ser Ala 185 190 195 Phe Gln Glu Cys Asp Glu Val Ile Gly Arg Glu Leu Glu Ala Ser 200 205 210 Gly Gln Met Gly Gly Cys Thr Ala Leu Val Ala Val Ser Leu Gln 215 220 225 Gly Lys Leu Tyr Met Ala Asn Ala Gly Asp Ser Arg Ala Ile Leu 230 235 240 Val Arg Arg Asp Glu Ile Arg Pro Leu Ser Phe Glu Phe Thr Pro 245 250 255 Glu Thr Glu Arg Gln Arg Ile Gln Gln Leu Ala Phe Val Tyr Pro 260 265 270 Glu Leu Leu Ala Gly Glu Phe Thr Arg Leu Glu Phe Pro Arg Arg 275 280 285 Leu Lys Gly Asp Asp Leu Gly Gln Lys Val Leu Phe Arg Asp His 290 295 300 His Met Ser Gly Trp Ser Tyr Lys Arg Val Glu Lys Ser Asp Leu 305 310 315 Lys Tyr Pro Leu Ile His Gly Gln Gly Arg Gln Ala Arg Leu Leu 320 325 330 Gly Thr Leu Ala Val Ser Arg Gly Leu Gly Asp His Gln Leu Arg 335 340 345 Val Leu Asp Thr Asn Ile Gln Leu Lys Pro Phe Leu Leu Ser Val 350 355 360 Pro Gln Val Thr Val Leu Asp Val Asp Gln Leu Glu Leu Gln Glu 365 370 375 Asp Asp Val Val Val Met Ala Thr Asp Gly Leu Trp Asp Val Leu 380 385 390 Ser Asn Glu Gln Val Ala Trp Leu Val Arg Ser Phe Leu Pro Gly 395 400 405 Asn Gln Glu Asp Pro His Arg Phe Ser Lys Leu Ala Gln Met Leu 410 415 420 Ile His Ser Thr Gln Gly Lys Glu Asp Ser Leu Thr Glu Glu Gly 425 430 435 Gln Val Ser Tyr Asp Asp Val Ser Val Phe Val Ile Pro Leu His 440 445 450 Ser Gln Gly Gln Glu Ser Ser Asp His 455 4 243 PRT Homo sapiens misc_feature Incyte ID No 4885040CD1 4 Met Glu His Ala Phe Thr Pro Leu Glu Pro Leu Leu Ser Thr Gly 1 5 10 15 Asn Leu Lys Tyr Cys Leu Val Ile Leu Asn Gln Pro Leu Asp Asn 20 25 30 Tyr Phe Arg His Leu Trp Asn Lys Ala Leu Leu Arg Ala Cys Ala 35 40 45 Asp Gly Gly Ala Asn Arg Leu Tyr Asp Ile Thr Glu Gly Glu Arg 50 55 60 Glu Ser Phe Leu Pro Glu Phe Ile Asn Gly Asp Phe Asp Ser Ile 65 70 75 Arg Pro Glu Val Arg Glu Tyr Tyr Ala Thr Lys Gly Cys Glu Leu 80 85 90 Ile Ser Thr Pro Asp Gln Asp His Thr Asp Phe Thr Lys Cys Leu 95 100 105 Lys Met Leu Gln Lys Lys Ile Glu Glu Lys Asp Leu Lys Val Asp 110 115 120 Val Ile Val Thr Leu Gly Gly Leu Ala Gly Arg Phe Asp Gln Ile 125 130 135 Met Ala Ser Val Asn Thr Leu Phe Gln Ala Thr His Ile Thr Pro 140 145 150 Phe Pro Ile Ile Ile Ile Gln Glu Glu Ser Leu Ile Tyr Leu Leu 155 160 165 Gln Pro Gly Lys His Arg Leu His Val Asp Thr Gly Met Glu Gly 170 175 180 Asp Trp Cys Gly Leu Ile Pro Val Gly Gln Pro Cys Met Gln Val 185 190 195 Thr Thr Thr Gly Leu Lys Trp Asn Leu Thr Asn Asp Val Leu Ala 200 205 210 Phe Gly Thr Leu Val Ser Thr Ser Asn Thr Tyr Asp Gly Ser Gly 215 220 225 Val Val Thr Val Glu Thr Asp His Pro Leu Leu Trp Thr Met Ala 230 235 240 Ile Lys Ser 5 632 PRT Homo sapiens misc_feature Incyte ID No 7484507CD1 5 Met Leu Gly Pro Gly Ser Asn Arg Arg Arg Pro Thr Gln Gly Glu 1 5 10 15 Arg Gly Pro Gly Ser Pro Gly Glu Pro Met Glu Lys Tyr Gln Val 20 25 30 Leu Tyr Gln Leu Asn Pro Gly Ala Leu Gly Val Asn Leu Val Val 35 40 45 Glu Glu Met Glu Thr Lys Val Lys His Val Ile Lys Gln Val Glu 50 55 60 Cys Met Asp Asp His Tyr Ala Ser Gln Ala Leu Glu Glu Leu Met 65 70 75 Pro Leu Leu Lys Leu Arg His Ala His Ile Ser Val Tyr Gln Glu 80 85 90 Leu Phe Ile Thr Trp Asn Gly Glu Ile Ser Ser Leu Tyr Leu Cys 95 100 105 Leu Val Met Glu Phe Asn Glu Leu Ser Phe Gln Glu Val Ile Glu 110 115 120 Asp Lys Arg Lys Ala Lys Lys Ile Ile Asp Ser Glu Trp Met Gln 125 130 135 Asn Val Leu Gly Gln Val Leu Asp Ala Leu Glu Tyr Leu His His 140 145 150 Leu Asp Ile Ile His Arg Asn Leu Lys Pro Ser Asn Ile Ile Leu 155 160 165 Ile Ser Ser Asp His Cys Lys Leu Gln Asp Leu Ser Ser Asn Val 170 175 180 Leu Met Thr Asp Lys Ala Lys Trp Asn Ile Arg Ala Glu Glu Asp 185 190 195 Pro Phe Arg Lys Ser Trp Met Ala Pro Glu Ala Leu Asn Phe Ser 200 205 210 Phe Ser Gln Lys Ser Asp Ile Trp Ser Leu Gly Cys Ile Ile Leu 215 220 225 Asp Met Thr Ser Cys Ser Phe Met Asp Gly Thr Glu Ala Met His 230 235 240 Leu Arg Lys Ser Leu Arg Gln Ser Pro Gly Ser Leu Lys Ala Val 245 250 255 Leu Lys Thr Met Glu Glu Lys Gln Ile Pro Asp Val Glu Thr Phe 260 265 270 Arg Asn Leu Leu Pro Leu Met Leu Gln Ile Asp Pro Ser Asp Arg 275 280 285 Ile Thr Ile Lys Asp Val Val His Ile Thr Phe Leu Arg Gly Ser 290 295 300 Phe Lys Ser Ser Cys Val Ser Leu Thr Leu His Arg Gln Met Val 305 310 315 Pro Ala Ser Ile Thr Asp Met Leu Leu Glu Gly Asn Val Ala Ser 320 325 330 Ile Leu Gly Asp Ala Gly Asp Thr Lys Gly Glu Arg Ala Leu Lys 335 340 345 Leu Leu Ser Met Ala Leu Ala Ser Tyr Cys Leu Val Pro Glu Gly 350 355 360 Ser Leu Phe Met Pro Leu Ala Leu Leu His Met His Asp Gln Trp 365 370 375 Leu Ser Cys Asp Gln Asp Arg Val Pro Gly Lys Arg Asp Phe Ala 380 385 390 Ser Leu Gly Lys Leu Gly Lys Leu Leu Gly Pro Ile Pro Lys Gly 395 400 405 Leu Pro Trp Pro Pro Glu Leu Val Glu Val Val Val Thr Thr Met 410 415 420 Glu Leu His Asp Arg Val Leu Asp Val Gln Leu Cys Ala Cys Ser 425 430 435 Leu Leu Leu His Leu Leu Gly Gln Gly Ile Ile Val Asn Lys Ala 440 445 450 Pro Leu Glu Lys Val Pro Asp Leu Ile Ser Gln Val Leu Ala Thr 455 460 465 Tyr Pro Ala Asp Gly Glu Met Ala Glu Ala Ser Cys Gly Val Phe 470 475 480 Trp Leu Leu Ser Leu Leu Gly Cys Ile Lys Glu Gln Gln Phe Glu 485 490 495 Gln Val Val Ala Leu Leu Leu Gln Ser Ile Arg Leu Cys Gln Asp 500 505 510 Arg Ala Leu Leu Val Asn Asn Ala Tyr Arg Gly Leu Ala Ser Leu 515 520 525 Val Lys Val Ser Glu Leu Ala Ala Phe Lys Val Val Val Gln Glu 530 535 540 Glu Gly Gly Ser Gly Leu Ser Leu Ile Lys Glu Thr Tyr Gln Leu 545 550 555 His Arg Asp Asp Pro Glu Val Val Glu Asn Val Gly Met Leu Leu 560 565 570 Val His Leu Ala Ser Tyr Glu Glu Ile Leu Pro Glu Leu Val Ser 575 580 585 Ser Ser Met Lys Ala Leu Leu Gln Glu Ile Lys Glu Arg Phe Thr 590 595 600 Ser Ser Leu Glu Leu Val Ser Cys Ala Glu Lys Val Leu Leu Arg 605 610 615 Leu Glu Ala Ala Thr Ser Pro Ser Pro Leu Gly Gly Glu Ala Ala 620 625 630 Gln Pro 6 1511 PRT Homo sapiens misc_feature Incyte ID No 7198931CD1 6 Met Ala Ala Ala Ala Gly Asn Arg Ala Ser Ser Ser Gly Phe Pro 1 5 10 15 Gly Ala Arg Ala Thr Ser Pro Glu Ala Gly Gly Gly Gly Gly Ala 20 25 30 Leu Lys Ala Ser Ser Ala Arg Ala Ala Ala Ala Gly Leu Leu Arg 35 40 45 Glu Ala Gly Ser Gly Gly Arg Glu Arg Ala Asp Trp Arg Arg Arg 50 55 60 Gln Leu Arg Lys Val Arg Ser Val Glu Leu Asp Gln Leu Pro Glu 65 70 75 Gln Pro Leu Phe Leu Ala Ala Ser Pro Pro Ala Ser Ser Thr Ser 80 85 90 Pro Ser Pro Glu Pro Ala Asp Ala Ala Gly Ser Gly Thr Gly Phe 95 100 105 Gln Pro Val Ala Val Pro Pro Pro His Gly Ala Ala Ser Arg Arg 110 115 120 Gly Ala His Leu Thr Glu Ser Val Ala Ala Pro Asp Ser Gly Ala 125 130 135 Ser Ser Pro Ala Ala Ala Glu Pro Gly Glu Lys Arg Ala Pro Ala 140 145 150 Ala Glu Pro Ser Pro Ala Ala Ala Pro Ala Gly Arg Glu Met Glu 155 160 165 Asn Lys Glu Thr Leu Lys Gly Leu His Lys Met Asp Asp Arg Pro 170 175 180 Glu Glu Arg Met Ile Arg Glu Lys Leu Lys Ala Thr Cys Met Pro 185 190 195 Ala Trp Lys His Glu Trp Leu Glu Arg Arg Asn Arg Arg Gly Pro 200 205 210 Val Val Val Lys Pro Ile Pro Val Lys Gly Asp Gly Ser Glu Met 215 220 225 Asn His Leu Ala Ala Glu Ser Pro Gly Glu Val Gln Ala Ser Ala 230 235 240 Ala Ser Pro Ala Ser Lys Gly Arg Arg Ser Pro Ser Pro Gly Asn 245 250 255 Ser Pro Ser Gly Arg Thr Val Lys Ser Glu Ser Pro Gly Val Arg 260 265 270 Arg Lys Arg Val Ser Pro Val Pro Phe Gln Ser Gly Arg Ile Thr 275 280 285 Pro Pro Arg Arg Ala Pro Ser Pro Asp Gly Phe Ser Pro Tyr Ser 290 295 300 Pro Glu Glu Thr Asn Arg Arg Val Asn Lys Val Met Arg Ala Arg 305 310 315 Leu Tyr Leu Leu Gln Gln Ile Gly Pro Asn Ser Phe Leu Ile Gly 320 325 330 Gly Asp Ser Pro Asp Asn Lys Tyr Arg Val Phe Ile Gly Pro Gln 335 340 345 Asn Cys Ser Cys Ala Arg Gly Thr Phe Cys Ile His Leu Leu Phe 350 355 360 Val Met Leu Arg Val Phe Gln Leu Glu Pro Ser Asp Pro Met Leu 365 370 375 Trp Arg Lys Thr Leu Lys Asn Phe Glu Val Glu Ser Leu Phe Gln 380 385 390 Lys Tyr His Ser Arg Arg Ser Ser Arg Ile Lys Ala Pro Ser Arg 395 400 405 Asn Thr Ile Gln Lys Phe Val Ser Arg Met Ser Asn Ser His Thr 410 415 420 Leu Ser Ser Ser Ser Thr Ser Thr Ser Ser Ser Glu Asn Ser Ile 425 430 435 Lys Asp Glu Glu Glu Gln Met Cys Pro Ile Cys Leu Leu Gly Met 440 445 450 Leu Asp Glu Glu Ser Leu Thr Val Cys Glu Asp Gly Cys Arg Asn 455 460 465 Lys Leu His His His Cys Met Ser Ile Trp Ala Glu Glu Cys Arg 470 475 480 Arg Asn Arg Glu Pro Leu Ile Cys Pro Leu Cys Arg Ser Lys Trp 485 490 495 Arg Ser His Asp Phe Tyr Ser His Glu Leu Ser Ser Pro Val Asp 500 505 510 Ser Pro Ser Ser Leu Arg Ala Ala Gln Gln Gln Thr Val Gln Gln 515 520 525 Gln Pro Leu Ala Gly Ser Arg Arg Asn Gln Glu Ser Asn Phe Asn 530 535 540 Leu Thr His Tyr Gly Thr Gln Gln Ile Pro Pro Ala Tyr Lys Asp 545 550 555 Leu Ala Glu Pro Trp Ile Gln Val Phe Gly Met Glu Leu Val Gly 560 565 570 Cys Leu Phe Ser Arg Asn Trp Asn Val Arg Glu Met Ala Leu Arg 575 580 585 Arg Leu Ser His Asp Val Ser Gly Ala Leu Leu Leu Ala Asn Gly 590 595 600 Glu Ser Thr Gly Asn Ser Gly Gly Ser Ser Gly Ser Ser Pro Ser 605 610 615 Gly Gly Ala Thr Ser Gly Ser Ser Gln Thr Ser Ile Ser Gly Asp 620 625 630 Val Val Glu Ala Cys Cys Ser Val Leu Ser Met Val Cys Ala Asp 635 640 645 Pro Val Tyr Lys Val Tyr Val Ala Ala Leu Lys Thr Leu Arg Ala 650 655 660 Met Leu Val Tyr Thr Pro Cys His Ser Leu Ala Glu Arg Ile Lys 665 670 675 Leu Gln Arg Leu Leu Gln Pro Val Val Asp Thr Ile Leu Val Lys 680 685 690 Cys Ala Asp Ala Asn Ser Arg Thr Ser Gln Leu Ser Ile Ser Thr 695 700 705 Leu Leu Glu Leu Cys Lys Gly Gln Ala Gly Glu Leu Ala Val Gly 710 715 720 Arg Glu Ile Leu Lys Ala Gly Ser Ile Gly Ile Gly Gly Val Asp 725 730 735 Tyr Val Leu Asn Cys Ile Leu Gly Asn Gln Thr Glu Ser Asn Asn 740 745 750 Trp Gln Glu Leu Leu Gly Arg Leu Cys Leu Ile Asp Arg Leu Leu 755 760 765 Leu Glu Phe Pro Ala Glu Phe Tyr Pro His Ile Val Ser Thr Asp 770 775 780 Val Ser Gln Ala Glu Pro Val Glu Ile Arg Tyr Lys Lys Leu Leu 785 790 795 Ser Leu Leu Thr Phe Ala Leu Gln Ser Ile Asn Asn Ser His Ser 800 805 810 Met Val Gly Lys Leu Ser Arg Arg Ile Tyr Leu Ser Ser Ala Arg 815 820 825 Met Val Thr Thr Val Pro His Val Phe Ser Lys Leu Leu Glu Met 830 835 840 Leu Ser Val Ser Ser Ser Thr His Phe Thr Arg Met Arg Arg Arg 845 850 855 Leu Met Ala Ile Thr Asp Glu Val Glu Ile Ala Glu Ala Ile Gln 860 865 870 Leu Gly Val Glu Asp Thr Leu Asp Gly Gln Gln Asp Ser Phe Leu 875 880 885 Gln Ala Ser Val Pro Asn Asn Tyr Leu Glu Thr Thr Glu Asn Ser 890 895 900 Ser Pro Glu Cys Thr Ile His Leu Glu Lys Thr Gly Lys Gly Leu 905 910 915 Cys Ala Thr Lys Leu Ser Ala Ser Ser Glu Asp Ile Ser Glu Arg 920 925 930 Leu Ala Ser Ile Ser Val Gly Pro Ser Ser Ser Thr Thr Thr Thr 935 940 945 Thr Thr Thr Glu Gln Pro Lys Pro Met Val Gln Thr Lys Gly Arg 950 955 960 Pro His Ser Gln Cys Leu Asn Ser Ser Pro Leu Ser His His Ser 965 970 975 Gln Leu Met Phe Pro Ala Leu Ser Thr Pro Ser Ser Ser Thr Pro 980 985 990 Ser Val Pro Ala Gly Thr Ala Thr Asp Val Ser Lys His Arg Leu 995 1000 1005 Gln Gly Phe Ile Pro Cys Arg Ile Pro Ser Ala Ser Pro Gln Thr 1010 1015 1020 Gln Arg Lys Phe Ser Leu Gln Phe His Arg Asn Cys Pro Glu Asn 1025 1030 1035 Lys Asp Ser Asp Lys Leu Ser Pro Val Phe Thr Gln Ser Arg Pro 1040 1045 1050 Leu Pro Ser Ser Asn Ile His Arg Pro Lys Pro Ser Arg Pro Thr 1055 1060 1065 Pro Gly Asn Thr Ser Lys Gln Gly Asp Pro Ser Lys Asn Ser Met 1070 1075 1080 Thr Leu Asp Leu Asn Ser Ser Ser Lys Cys Asp Asp Ser Phe Gly 1085 1090 1095 Cys Ser Ser Asn Ser Ser Asn Ala Val Ile Pro Ser Asp Glu Thr 1100 1105 1110 Val Phe Thr Pro Val Glu Glu Lys Cys Arg Leu Asp Val Asn Thr 1115 1120 1125 Glu Leu Asn Ser Ser Ile Glu Asp Leu Leu Glu Ala Ser Met Pro 1130 1135 1140 Ser Ser Asp Thr Thr Val Thr Phe Lys Ser Glu Val Ala Val Leu 1145 1150 1155 Ser Pro Glu Lys Ala Glu Asn Asp Asp Thr Tyr Lys Asp Asp Val 1160 1165 1170 Asn His Asn Gln Lys Cys Lys Glu Lys Met Glu Ala Glu Glu Glu 1175 1180 1185 Glu Ala Leu Ala Ile Ala Met Ala Met Ser Ala Ser Gln Asp Ala 1190 1195 1200 Leu Pro Ile Val Pro Gln Leu Gln Val Glu Asn Gly Glu Asp Ile 1205 1210 1215 Ile Ile Ile Gln Gln Asp Thr Pro Glu Thr Leu Pro Gly His Thr 1220 1225 1230 Lys Ala Lys Gln Pro Tyr Arg Glu Asp Thr Glu Trp Leu Lys Gly 1235 1240 1245 Gln Gln Ile Gly Leu Gly Ala Phe Ser Ser Cys Tyr Gln Ala Gln 1250 1255 1260 Asp Val Gly Thr Gly Thr Leu Met Ala Val Lys Gln Val Thr Tyr 1265 1270 1275 Val Arg Asn Thr Ser Ser Glu Gln Glu Glu Val Val Glu Ala Leu 1280 1285 1290 Arg Glu Glu Ile Arg Met Met Ser His Leu Asn His Pro Asn Ile 1295 1300 1305 Ile Arg Met Leu Gly Ala Thr Cys Glu Lys Ser Asn Tyr Asn Leu 1310 1315 1320 Phe Ile Glu Trp Met Ala Gly Gly Ser Val Ala His Leu Leu Ser 1325 1330 1335 Lys Tyr Gly Ala Phe Lys Glu Ser Val Val Ile Asn Tyr Thr Glu 1340 1345 1350 Gln Leu Leu Arg Gly Leu Ser Tyr Leu His Glu Asn Gln Ile Ile 1355 1360 1365 His Arg Asp Val Lys Gly Ala Asn Leu Leu Ile Asp Ser Thr Gly 1370 1375 1380 Gln Arg Leu Arg Ile Ala Asp Phe Gly Ala Ala Ala Arg Leu Ala 1385 1390 1395 Ser Lys Gly Thr Gly Ala Gly Glu Phe Gln Gly Gln Leu Leu Gly 1400 1405 1410 Thr Ile Ala Phe Met Ala Pro Glu Val Leu Arg Gly Gln Gln Tyr 1415 1420 1425 Gly Arg Ser Cys Asp Val Trp Ser Val Gly Cys Ala Ile Ile Glu 1430 1435 1440 Met Ala Cys Ala Lys Pro Pro Trp Asn Ala Glu Lys His Ser Asn 1445 1450 1455 His Leu Ala Leu Ile Phe Lys Ile Ala Ser Ala Thr Thr Ala Pro 1460 1465 1470 Ser Ile Pro Ser His Leu Ser Pro Gly Leu Arg Asp Val Ala Leu 1475 1480 1485 Arg Cys Leu Glu Leu Gln Pro Gln Asp Arg Pro Pro Ser Arg Glu 1490 1495 1500 Leu Leu Lys His Pro Val Phe Arg Thr Thr Trp 1505 1510 7 830 PRT Homo sapiens misc_feature Incyte ID No 7482905CD1 7 Met Lys Ala Glu Gln Met Lys Arg Gln Glu Lys Glu Arg Leu Glu 1 5 10 15 Arg Ile Asn Arg Ala Arg Glu Gln Gly Trp Arg Asn Val Leu Ser 20 25 30 Ala Gly Gly Ser Gly Glu Val Lys Ala Pro Phe Leu Gly Ser Gly 35 40 45 Gly Thr Ile Ala Pro Ser Ser Phe Ser Ser Arg Gly Gln Tyr Glu 50 55 60 His Tyr His Ala Ile Phe Asp Gln Met Gln Gln Gln Arg Ala Glu 65 70 75 Asp Asn Glu Ala Lys Trp Lys Arg Glu Ile Tyr Gly Arg Gly Leu 80 85 90 Pro Glu Arg Gln Lys Gly Gln Leu Ala Val Glu Arg Ala Lys Gln 95 100 105 Val Glu Glu Phe Leu Gln Arg Lys Arg Glu Ala Met Gln Asn Lys 110 115 120 Ala Arg Ala Glu Gly His Met Val Tyr Leu Ala Arg Leu Arg Gln 125 130 135 Ile Arg Leu Gln Asn Phe Asn Glu Arg Gln Gln Ile Lys Ala Lys 140 145 150 Leu Arg Gly Glu Lys Lys Glu Ala Asn His Ser Glu Gly Gln Glu 155 160 165 Gly Ser Glu Glu Ala Asp Met Arg Arg Lys Lys Ile Glu Ser Leu 170 175 180 Lys Ala His Ala Asn Ala Arg Ala Ala Val Leu Lys Glu Gln Leu 185 190 195 Glu Arg Lys Arg Lys Glu Ala Tyr Glu Arg Glu Lys Lys Val Trp 200 205 210 Glu Glu His Leu Val Ala Lys Gly Val Lys Ser Ser Asp Val Ser 215 220 225 Pro Pro Leu Gly Gln His Glu Thr Gly Gly Ser Pro Ser Lys Gln 230 235 240 Gln Met Arg Ser Val Ile Ser Val Thr Ser Ala Leu Lys Glu Val 245 250 255 Gly Val Asp Ser Ser Leu Thr Asp Thr Arg Glu Thr Ser Glu Glu 260 265 270 Met Gln Lys Thr Asn Asn Ala Ile Ser Ser Lys Arg Glu Ile Leu 275 280 285 Arg Arg Leu Asn Glu Asn Leu Lys Ala Gln Glu Asp Glu Lys Gly 290 295 300 Lys Gln Asn Leu Ser Asp Thr Phe Glu Ile Asn Val His Glu Asp 305 310 315 Ala Lys Glu His Glu Lys Glu Lys Ser Val Ser Ser Asp Arg Lys 320 325 330 Lys Trp Glu Ala Gly Gly Gln Leu Val Ile Pro Leu Asp Glu Leu 335 340 345 Thr Leu Asp Thr Ser Phe Ser Thr Thr Glu Arg His Thr Val Gly 350 355 360 Glu Val Ile Lys Leu Gly Pro Asn Gly Ser Pro Arg Arg Ala Trp 365 370 375 Gly Lys Ser Pro Thr Asp Ser Val Leu Lys Ile Leu Gly Glu Ala 380 385 390 Glu Leu Gln Leu Gln Thr Glu Leu Leu Glu Asn Thr Thr Ile Arg 395 400 405 Ser Glu Ile Ser Pro Glu Gly Glu Lys Tyr Lys Pro Leu Ile Thr 410 415 420 Gly Glu Lys Lys Val Gln Cys Ile Ser His Glu Ile Asn Pro Ser 425 430 435 Ala Ile Val Asp Ser Pro Val Glu Thr Lys Ser Pro Glu Phe Ser 440 445 450 Glu Ala Ser Pro Gln Met Ser Leu Lys Leu Glu Gly Asn Leu Glu 455 460 465 Glu Pro Asp Asp Leu Glu Thr Glu Ile Leu Gln Glu Pro Ser Gly 470 475 480 Thr Asn Lys Asp Glu Ser Leu Pro Cys Thr Ile Thr Asp Val Trp 485 490 495 Ile Ser Glu Glu Lys Glu Thr Lys Glu Thr Gln Ser Ala Asp Arg 500 505 510 Ile Thr Ile Gln Glu Asn Glu Val Ser Glu Asp Gly Val Ser Ser 515 520 525 Thr Val Asp Gln Leu Ser Asp Ile His Ile Glu Pro Gly Thr Asn 530 535 540 Asp Ser Gln His Ser Lys Cys Asp Val Asp Lys Ser Val Gln Pro 545 550 555 Glu Pro Phe Phe His Lys Val Val His Ser Glu His Leu Asn Leu 560 565 570 Val Pro Gln Val Gln Ser Val Gln Cys Ser Pro Glu Glu Ser Phe 575 580 585 Ala Phe Arg Ser His Ser His Leu Pro Pro Lys Asn Lys Asn Lys 590 595 600 Asn Ser Leu Leu Ile Gly Leu Ser Thr Gly Leu Phe Asp Ala Asn 605 610 615 Asn Pro Lys Met Leu Arg Thr Cys Ser Leu Pro Asp Leu Ser Lys 620 625 630 Leu Phe Arg Thr Leu Met Asp Val Pro Thr Val Gly Asp Val Arg 635 640 645 Gln Asp Asn Leu Glu Ile Asp Glu Ile Glu Asp Glu Asn Ile Lys 650 655 660 Glu Gly Pro Ser Asp Ser Glu Asp Ile Val Phe Glu Glu Thr Asp 665 670 675 Thr Asp Leu Gln Glu Leu Gln Ala Ser Met Glu Gln Leu Leu Arg 680 685 690 Glu Gln Pro Gly Glu Glu Tyr Ser Glu Glu Glu Glu Ser Val Leu 695 700 705 Lys Asn Ser Asp Val Glu Pro Thr Ala Asn Gly Thr Asp Val Ala 710 715 720 Asp Glu Asp Asp Asn Pro Ser Ser Glu Ser Ala Leu Asn Glu Glu 725 730 735 Trp His Ser Asp Asn Ser Asp Gly Glu Ile Ala Ser Glu Cys Glu 740 745 750 Cys Asp Ser Val Phe Asn His Leu Glu Glu Leu Arg Leu His Leu 755 760 765 Glu Gln Glu Met Gly Phe Glu Lys Phe Phe Glu Val Tyr Glu Lys 770 775 780 Ile Lys Ala Ile His Glu Asp Glu Asp Glu Asn Ile Glu Ile Cys 785 790 795 Ser Lys Ile Val Gln Asn Ile Leu Gly Asn Glu His Gln His Leu 800 805 810 Tyr Ala Lys Ile Leu His Leu Val Met Ala Asp Gly Ala Tyr Gln 815 820 825 Glu Asp Asn Asp Glu 830 8 455 PRT Homo sapiens misc_feature Incyte ID No 7483019CD1 8 Met Arg Ile Val Cys Leu Val Lys Asn Gln Gln Pro Leu Gly Ala 1 5 10 15 Thr Ile Lys Arg His Glu Met Thr Gly Asp Ile Leu Val Ala Arg 20 25 30 Ile Ile His Gly Gly Leu Ala Glu Arg Ser Gly Leu Leu Tyr Ala 35 40 45 Gly Asp Lys Leu Val Glu Val Asn Gly Val Ser Val Glu Gly Leu 50 55 60 Asp Pro Glu Gln Val Ile His Ile Leu Ala Met Ser Arg Gly Thr 65 70 75 Ile Met Phe Lys Val Val Pro Val Ser Asp Pro Pro Val Asn Ser 80 85 90 Gln Gln Met Val Tyr Val Arg Ala Met Thr Glu Tyr Trp Pro Gln 95 100 105 Glu Asp Pro Asp Ile Pro Cys Met Asp Ala Gly Leu Pro Phe Gln 110 115 120 Lys Gly Asp Ile Leu Gln Ile Val Asp Gln Asn Asp Ala Leu Trp 125 130 135 Trp Gln Ala Arg Lys Ile Ser Asp Pro Ala Thr Cys Ala Gly Leu 140 145 150 Val Pro Ser Asn His Leu Leu Lys Arg Lys Gln Arg Glu Phe Trp 155 160 165 Trp Ser Gln Pro Tyr Gln Pro His Thr Cys Leu Lys Ser Thr Leu 170 175 180 Tyr Lys Glu Glu Phe Val Gly Tyr Gly Gln Lys Phe Phe Ile Ala 185 190 195 Gly Phe Arg Arg Ser Met Arg Leu Cys Arg Arg Lys Ser His Leu 200 205 210 Ser Pro Leu His Ala Ser Val Cys Cys Thr Gly Ser Cys Tyr Ser 215 220 225 Ala Val Gly Ala Pro Tyr Glu Glu Val Val Arg Tyr Gln Arg Arg 230 235 240 Pro Ser Asp Lys Tyr Arg Leu Ile Val Leu Met Gly Pro Ser Gly 245 250 255 Val Gly Val Asn Glu Leu Arg Arg Gln Leu Ile Glu Phe Asn Pro 260 265 270 Ser His Phe Gln Ser Ala Val Pro His Thr Thr Arg Thr Lys Lys 275 280 285 Ser Tyr Glu Thr Asn Gly Arg Glu Tyr His Tyr Val Ser Lys Glu 290 295 300 Thr Phe Glu Asn Leu Ile Tyr Ser His Arg Met Leu Glu Tyr Gly 305 310 315 Glu Tyr Lys Gly His Leu Tyr Gly Thr Ser Val Gly Ala Val Gln 320 325 330 Thr Val Leu Val Glu Gly Lys Ile Cys Val Met Asp Leu Glu Pro 335 340 345 Gln Asp Ile Gln Gly Val Arg Thr His Glu Leu Lys Pro Tyr Val 350 355 360 Ile Phe Ile Lys Pro Ser Asn Met Arg Cys Met Lys Gln Ser Arg 365 370 375 Lys Asn Ala Lys Val Ile Thr Asp Tyr Tyr Val Asp Met Lys Phe 380 385 390 Lys Asp Glu Asp Leu Gln Glu Met Glu Asn Leu Ala Gln Arg Met 395 400 405 Glu Thr Gln Phe Gly Gln Phe Phe Asp His Val Ile Val Asn Asp 410 415 420 Ser Leu His Asp Ala Cys Ala Gln Leu Leu Ser Ala Ile Gln Lys 425 430 435 Ala Gln Glu Glu Pro Gln Trp Val Pro Ala Thr Trp Ile Ser Ser 440 445 450 Asp Thr Glu Ser Gln 455 9 1720 PRT Homo sapiens misc_feature Incyte ID No 5455490CD1 9 Met Met Lys Arg Arg Arg Glu Arg Leu Gly Ala Pro Cys Leu Arg 1 5 10 15 Ile Gln Ile Ser Thr Leu Cys Arg Gly Ala Glu Val Asn Gln His 20 25 30 Met Phe Ser Pro Thr Ser Ala Pro Ala Leu Phe Leu Thr Lys Val 35 40 45 Pro Phe Ser Ala Asp Cys Ala Leu Ala Thr Ser Pro Leu Ala Ile 50 55 60 Phe Leu Asn Pro Arg Ala His Ser Ser Pro Gly Thr Pro Cys Ser 65 70 75 Ser Arg Pro Leu Pro Trp Ser Cys Arg Thr Ser Asn Arg Lys Ser 80 85 90 Leu Ile Val Thr Ser Ser Thr Ser Pro Thr Leu Pro Arg Pro His 95 100 105 Ser Pro Leu His Gly His Thr Gly Asn Ser Pro Leu Asp Ser Pro 110 115 120 Arg Asn Phe Ser Pro Asn Ala Pro Ala His Phe Ser Phe Val Pro 125 130 135 Ala Arg Ser His Ser His Arg Ala Asp Arg Thr Asp Gly Arg Arg 140 145 150 Trp Ser Leu Ala Ser Leu Pro Ser Ser Gly Tyr Gly Thr Asn Thr 155 160 165 Pro Ser Ser Thr Val Ser Ser Ser Cys Ser Ser Gln Glu Lys Leu 170 175 180 His Gln Leu Pro Phe Gln Pro Thr Ala Asp Glu Leu His Phe Leu 185 190 195 Thr Lys His Phe Ser Thr Glu Ser Val Pro Asp Glu Glu Gly Arg 200 205 210 Gln Ser Pro Ala Met Arg Pro Arg Ser Arg Ser Leu Ser Pro Gly 215 220 225 Arg Ser Pro Val Ser Phe Asp Ser Glu Ile Ile Met Met Asn His 230 235 240 Val Tyr Lys Glu Arg Phe Pro Lys Ala Thr Ala Gln Met Glu Glu 245 250 255 Arg Leu Ala Glu Phe Ile Ser Ser Asn Thr Pro Asp Ser Val Leu 260 265 270 Pro Leu Ala Asp Gly Ala Leu Ser Phe Ile His His Gln Val Ile 275 280 285 Glu Met Ala Arg Asp Cys Leu Asp Lys Ser Arg Ser Gly Leu Ile 290 295 300 Thr Ser Gln Tyr Phe Tyr Glu Leu Gln Glu Asn Leu Glu Lys Leu 305 310 315 Leu Gln Asp Ala His Glu Arg Ser Glu Ser Ser Glu Val Ala Phe 320 325 330 Val Met Gln Leu Val Lys Lys Leu Met Ile Ile Ile Ala Arg Pro 335 340 345 Ala Arg Leu Leu Glu Cys Leu Glu Phe Asp Pro Glu Glu Phe Tyr 350 355 360 His Leu Leu Glu Ala Ala Glu Gly His Ala Lys Glu Gly Gln Gly 365 370 375 Ile Lys Cys Asp Ile Pro Arg Tyr Ile Val Ser Gln Leu Gly Leu 380 385 390 Thr Arg Asp Pro Leu Glu Glu Met Ala Gln Leu Ser Ser Cys Asp 395 400 405 Ser Pro Asp Thr Pro Glu Thr Asp Asp Ser Ile Glu Gly His Gly 410 415 420 Ala Ser Leu Pro Ser Lys Lys Thr Pro Ser Glu Glu Asp Phe Glu 425 430 435 Thr Ile Lys Leu Ile Ser Asn Gly Ala Tyr Gly Ala Val Phe Leu 440 445 450 Val Arg His Lys Ser Thr Arg Gln Arg Phe Ala Met Lys Lys Ile 455 460 465 Asn Lys Gln Asn Leu Ile Leu Arg Asn Gln Ile Gln Gln Ala Phe 470 475 480 Val Glu Arg Asp Ile Leu Thr Phe Ala Glu Asn Pro Phe Val Val 485 490 495 Ser Met Phe Cys Ser Phe Asp Thr Lys Arg His Leu Cys Met Val 500 505 510 Met Glu Tyr Val Glu Gly Gly Asp Cys Ala Thr Leu Leu Lys Asn 515 520 525 Ile Gly Ala Leu Pro Val Asp Met Val Arg Leu Tyr Phe Ala Glu 530 535 540 Thr Val Leu Ala Leu Glu Tyr Leu His Asn Tyr Gly Ile Val His 545 550 555 Arg Asp Leu Lys Pro Asp Asn Leu Leu Ile Thr Ser Met Gly His 560 565 570 Ile Lys Leu Thr Asp Phe Gly Leu Ser Lys Ile Gly Leu Met Ser 575 580 585 Leu Thr Thr Asn Leu Tyr Glu Gly His Ile Glu Lys Asp Ala Arg 590 595 600 Glu Phe Leu Asp Lys Gln Val Cys Gly Thr Pro Glu Tyr Ile Ala 605 610 615 Pro Glu Val Ile Leu Arg Gln Gly Tyr Gly Lys Pro Val Asp Trp 620 625 630 Trp Ala Met Gly Ile Ile Leu Tyr Glu Phe Leu Val Gly Cys Val 635 640 645 Pro Phe Phe Gly Asp Thr Pro Glu Glu Leu Phe Gly Gln Val Ile 650 655 660 Ser Asp Glu Ile Val Trp Pro Glu Gly Asp Glu Ala Leu Pro Pro 665 670 675 Asp Ala Gln Asp Leu Thr Ser Lys Leu Leu His Gln Asn Pro Leu 680 685 690 Glu Arg Leu Gly Thr Gly Ser Ala Tyr Glu Val Lys Gln His Pro 695 700 705 Phe Phe Thr Gly Leu Asp Trp Thr Gly Leu Leu Arg Gln Lys Ala 710 715 720 Glu Phe Ile Pro Gln Leu Glu Ser Glu Asp Asp Thr Ser Tyr Phe 725 730 735 Asp Thr Arg Ser Glu Arg Tyr His His Met Asp Ser Glu Asp Glu 740 745 750 Glu Glu Val Ser Glu Asp Gly Cys Leu Glu Ile Arg Gln Phe Ser 755 760 765 Ser Cys Ser Pro Arg Phe Asn Lys Val Tyr Ser Ser Met Glu Arg 770 775 780 Leu Ser Leu Leu Glu Glu Arg Arg Thr Pro Pro Pro Thr Lys Arg 785 790 795 Ser Leu Ser Glu Glu Lys Glu Asp His Ser Asp Gly Leu Ala Gly 800 805 810 Leu Lys Gly Arg Asp Arg Ser Trp Val Ile Gly Ser Pro Glu Ile 815 820 825 Leu Arg Lys Arg Leu Ser Val Ser Glu Ser Ser His Thr Glu Ser 830 835 840 Asp Ser Ser Pro Pro Met Thr Val Arg Arg Arg Cys Ser Gly Leu 845 850 855 Leu Asp Ala Pro Arg Phe Pro Glu Gly Pro Glu Glu Ala Ser Ser 860 865 870 Thr Leu Arg Arg Gln Pro Gln Glu Gly Ile Trp Val Leu Thr Pro 875 880 885 Pro Ser Gly Glu Gly Val Ser Gly Pro Val Thr Glu His Ser Gly 890 895 900 Glu Gln Arg Pro Lys Leu Asp Glu Glu Ala Val Gly Arg Ser Ser 905 910 915 Gly Ser Ser Pro Ala Met Glu Thr Arg Gly Arg Gly Thr Ser Gln 920 925 930 Leu Ala Glu Gly Ala Thr Ala Lys Ala Ile Ser Asp Leu Ala Val 935 940 945 Arg Arg Ala Arg His Arg Leu Leu Ser Gly Asp Ser Thr Glu Lys 950 955 960 Arg Thr Ala Arg Pro Val Asn Lys Val Ile Lys Ser Ala Ser Ala 965 970 975 Thr Ala Leu Ser Leu Leu Ile Pro Ser Glu His His Thr Cys Ser 980 985 990 Pro Leu Ala Ser Pro Met Ser Pro His Ser Gln Ser Ser Asn Pro 995 1000 1005 Ser Ser Arg Asp Ser Ser Pro Ser Arg Asp Phe Leu Pro Ala Leu 1010 1015 1020 Gly Ser Met Arg Pro Pro Ile Ile Ile His Arg Ala Gly Lys Lys 1025 1030 1035 Tyr Gly Phe Thr Leu Arg Ala Ile Arg Val Tyr Met Gly Asp Ser 1040 1045 1050 Asp Val Tyr Thr Val His His Met Val Trp His Val Glu Asp Gly 1055 1060 1065 Gly Pro Ala Ser Glu Ala Gly Leu Arg Gln Gly Asp Leu Ile Thr 1070 1075 1080 His Val Asn Gly Glu Pro Val His Gly Leu Val His Thr Glu Val 1085 1090 1095 Val Glu Leu Ile Leu Lys Ser Gly Asn Lys Val Ala Ile Ser Thr 1100 1105 1110 Thr Pro Leu Glu Asn Thr Ser Ile Lys Val Gly Pro Ala Arg Lys 1115 1120 1125 Gly Ser Tyr Lys Ala Lys Met Ala Arg Arg Ser Lys Arg Ser Arg 1130 1135 1140 Gly Lys Asp Gly Gln Glu Ser Arg Lys Arg Ser Ser Leu Phe Arg 1145 1150 1155 Lys Ile Thr Lys Gln Ala Ser Leu Leu His Thr Ser Arg Ser Leu 1160 1165 1170 Ser Ser Leu Asn Arg Ser Leu Ser Ser Gly Glu Ser Gly Pro Gly 1175 1180 1185 Ser Pro Thr His Ser His Ser Leu Ser Pro Arg Ser Pro Thr Gln 1190 1195 1200 Gly Tyr Arg Val Thr Pro Asp Ala Val His Ser Val Gly Gly Asn 1205 1210 1215 Ser Ser Gln Ser Ser Ser Pro Ser Ser Ser Val Pro Ser Ser Pro 1220 1225 1230 Ala Gly Ser Gly His Thr Arg Pro Ser Ser Leu His Gly Leu Ala 1235 1240 1245 Pro Lys Leu Gln Arg Gln Tyr Arg Ser Pro Arg Arg Lys Ser Ala 1250 1255 1260 Gly Ser Ile Pro Leu Ser Pro Leu Ala His Thr Pro Ser Pro Pro 1265 1270 1275 Pro Pro Thr Ala Ser Pro Gln Arg Ser Pro Ser Pro Leu Ser Gly 1280 1285 1290 His Val Ala Gln Ala Phe Pro Thr Lys Leu His Leu Ser Pro Pro 1295 1300 1305 Leu Gly Arg Gln Leu Ser Arg Pro Lys Ser Ala Glu Pro Pro Arg 1310 1315 1320 Ser Pro Leu Leu Lys Arg Val Gln Ser Ala Glu Lys Leu Ala Ala 1325 1330 1335 Ala Leu Ala Ala Ser Glu Lys Lys Leu Ala Thr Ser Arg Lys His 1340 1345 1350 Ser Leu Asp Leu Pro His Ser Glu Leu Lys Lys Glu Leu Pro Pro 1355 1360 1365 Arg Glu Val Ser Pro Leu Glu Val Val Gly Ala Arg Ser Val Leu 1370 1375 1380 Ser Gly Lys Gly Ala Leu Pro Gly Lys Gly Val Leu Gln Pro Ala 1385 1390 1395 Pro Ser Arg Ala Leu Gly Thr Leu Arg Gln Asp Arg Ala Glu Arg 1400 1405 1410 Arg Glu Ser Leu Gln Lys Gln Glu Ala Ile Arg Glu Val Asp Ser 1415 1420 1425 Ser Glu Asp Asp Thr Glu Glu Gly Pro Glu Asn Ser Gln Gly Ala 1430 1435 1440 Gln Glu Leu Ser Leu Ala Pro His Pro Glu Val Ser Gln Ser Val 1445 1450 1455 Ala Pro Lys Gly Ala Gly Glu Ser Gly Glu Glu Asp Pro Phe Pro 1460 1465 1470 Ser Arg Asp Pro Arg Ser Leu Gly Pro Met Val Pro Ser Leu Leu 1475 1480 1485 Thr Gly Ile Thr Leu Gly Pro Pro Arg Met Glu Ser Pro Ser Gly 1490 1495 1500 Pro His Arg Arg Leu Gly Ser Pro Gln Ala Ile Glu Glu Ala Ala 1505 1510 1515 Ser Ser Ser Ser Ala Gly Pro Asn Leu Gly Gln Ser Gly Ala Thr 1520 1525 1530 Asp Pro Ile Pro Pro Glu Gly Cys Trp Lys Ala Gln His Leu His 1535 1540 1545 Thr Gln Ala Leu Thr Ala Leu Ser Pro Ser Thr Ser Gly Leu Thr 1550 1555 1560 Pro Thr Ser Ser Cys Ser Pro Pro Ser Ser Thr Ser Gly Lys Leu 1565 1570 1575 Ser Met Trp Ser Trp Lys Ser Leu Ile Glu Gly Pro Asp Arg Ala 1580 1585 1590 Ser Pro Ser Arg Lys Ala Thr Met Ala Gly Gly Leu Ala Asn Leu 1595 1600 1605 Gln Asp Leu Glu Asn Thr Thr Pro Ala Gln Pro Lys Asn Leu Ser 1610 1615 1620 Pro Arg Glu Gln Gly Lys Thr Gln Pro Pro Ser Ala Pro Arg Leu 1625 1630 1635 Ala His Pro Ser Tyr Glu Asp Pro Ser Gln Gly Trp Leu Trp Glu 1640 1645 1650 Ser Glu Cys Ala Gln Ala Val Lys Glu Asp Pro Ala Leu Ser Ile 1655 1660 1665 Thr Gln Val Pro Asp Ala Ser Gly Asp Arg Arg Gln Asp Val Pro 1670 1675 1680 Cys Arg Gly Cys Pro Leu Thr Gln Lys Ser Glu Pro Ser Leu Arg 1685 1690 1695 Arg Gly Gln Glu Pro Gly Gly His Gln Lys His Arg Asp Leu Ala 1700 1705 1710 Leu Val Pro Asp Glu Leu Leu Lys Gln Thr 1715 1720 10 449 PRT Homo sapiens misc_feature Incyte ID No 5547067CD1 10 Met Leu Met Gly Phe Cys Arg Leu Glu Glu Ala Gly Leu Val Ser 1 5 10 15 Arg Ser Ile Arg Glu Arg Asn Cys Leu Tyr Asn Trp Asp Ser Arg 20 25 30 Phe Ser Arg Glu Arg Arg Gln Arg Leu Gly Met Gly Ala Val Ser 35 40 45 Cys Arg Gln Gly Gln His Thr Gln Gln Gly Glu His Thr Arg Val 50 55 60 Ala Val Pro His Lys Gly Gly Asn Ile Arg Gly Pro Trp Ala Arg 65 70 75 Gly Trp Lys Ser Leu Trp Thr Gly Leu Gly Thr Ile Arg Ser Asp 80 85 90 Leu Glu Glu Leu Trp Glu Leu Arg Gly His His Tyr Leu His Gln 95 100 105 Glu Ser Leu Lys Pro Ala Pro Val Leu Val Glu Lys Pro Leu Pro 110 115 120 Glu Trp Pro Val Pro Gln Phe Ile Asn Leu Phe Leu Pro Glu Phe 125 130 135 Pro Ile Arg Pro Ile Arg Gly Gln Gln Gln Leu Lys Ile Leu Gly 140 145 150 Leu Val Ala Lys Gly Ser Phe Gly Thr Val Leu Lys Val Leu Asp 155 160 165 Cys Thr Gln Lys Ala Val Phe Ala Val Lys Val Val Pro Lys Val 170 175 180 Lys Val Leu Gln Arg Asp Thr Val Arg Gln Cys Lys Glu Glu Val 185 190 195 Ser Ile Gln Arg Gln Ile Asn His Pro Phe Val His Ser Leu Gly 200 205 210 Asp Ser Trp Gln Gly Lys Arg His Leu Phe Ile Met Cys Ser Tyr 215 220 225 Cys Ser Thr Asp Leu Tyr Ser Leu Trp Ser Ala Val Gly Cys Phe 230 235 240 Pro Glu Ala Ser Ile Arg Leu Phe Ala Ala Glu Leu Val Leu Val 245 250 255 Leu Cys Tyr Leu His Asp Leu Gly Ile Met His Arg Asp Val Lys 260 265 270 Met Glu Asn Ile Leu Leu Asp Glu Arg Gly His Leu Lys Leu Thr 275 280 285 Asp Phe Gly Leu Ser Arg His Val Pro Gln Gly Ala Gln Ala Tyr 290 295 300 Thr Ile Cys Gly Thr Leu Gln Tyr Met Ala Pro Glu Val Leu Ser 305 310 315 Gly Gly Pro Tyr Asn His Ala Ala Asp Trp Trp Ser Leu Gly Val 320 325 330 Leu Leu Phe Ser Leu Ala Thr Gly Lys Phe Pro Val Ala Ala Glu 335 340 345 Arg Asp His Val Ala Met Leu Ala Ser Val Thr His Ser Asp Ser 350 355 360 Glu Ile Pro Ala Ser Leu Asn Gln Gly Leu Ser Leu Leu Leu His 365 370 375 Glu Leu Leu Cys Gln Asn Pro Leu His Arg Leu Arg Tyr Leu His 380 385 390 His Phe Gln Val His Pro Phe Phe Arg Gly Val Ala Phe Asp Pro 395 400 405 Glu Leu Leu Gln Lys Gln Pro Val Asn Phe Val Thr Glu Thr Gln 410 415 420 Ala Thr Gln Pro Ser Ser Ala Glu Thr Met Pro Phe Asp Asp Phe 425 430 435 Asp Cys Asp Leu Glu Ser Phe Leu Leu Tyr Pro Ile Pro Ala 440 445 11 358 PRT Homo sapiens misc_feature Incyte ID No 71675660CD1 11 Met Asp Asp Ala Thr Val Leu Arg Lys Lys Gly Tyr Ile Val Gly 1 5 10 15 Ile Asn Leu Gly Lys Gly Ser Tyr Ala Lys Val Lys Ser Ala Tyr 20 25 30 Ser Glu Arg Leu Lys Phe Asn Val Ala Val Lys Ile Ile Asp Arg 35 40 45 Lys Lys Thr Pro Thr Asp Phe Val Glu Arg Phe Leu Pro Arg Glu 50 55 60 Met Asp Ile Leu Ala Thr Val Asn His Gly Ser Ile Ile Lys Thr 65 70 75 Tyr Glu Ile Phe Glu Thr Ser Asp Gly Arg Ile Tyr Ile Ile Met 80 85 90 Glu Leu Gly Val Gln Gly Asp Leu Leu Glu Phe Ile Lys Cys Gln 95 100 105 Gly Ala Leu His Glu Asp Val Ala Arg Lys Met Phe Arg Gln Leu 110 115 120 Ser Ser Ala Val Lys Tyr Cys His Asp Leu Asp Ile Val His Arg 125 130 135 Asp Leu Lys Cys Glu Asn Leu Leu Leu Asp Lys Asp Phe Asn Ile 140 145 150 Lys Leu Ser Asp Phe Gly Phe Ser Lys Arg Cys Leu Arg Asp Ser 155 160 165 Asn Gly Arg Ile Ile Leu Ser Lys Thr Phe Cys Gly Ser Ala Ala 170 175 180 Tyr Ala Ala Pro Glu Val Leu Gln Ser Ile Pro Tyr Gln Pro Lys 185 190 195 Val Tyr Asp Ile Trp Ser Leu Gly Val Ile Leu Tyr Ile Met Val 200 205 210 Cys Gly Ser Met Pro Tyr Asp Asp Ser Asp Ile Arg Lys Met Leu 215 220 225 Arg Ile Gln Lys Glu His Arg Val Asp Phe Pro Arg Ser Lys Asn 230 235 240 Leu Thr Cys Glu Cys Lys Asp Leu Ile Tyr Arg Met Leu Gln Pro 245 250 255 Asp Val Ser Gln Arg Leu His Ile Asp Glu Ile Leu Ser His Ser 260 265 270 Trp Leu Gln Pro Pro Lys Pro Lys Ala Met Ser Ser Ala Ser Phe 275 280 285 Lys Arg Glu Gly Glu Gly Lys Tyr Arg Ala Glu Cys Lys Leu Asp 290 295 300 Thr Lys Thr Gly Leu Arg Pro Asp His Arg Pro Asp His Lys Leu 305 310 315 Gly Ala Lys Thr Gln His Arg Leu Leu Val Val Pro Glu Asn Glu 320 325 330 Asn Arg Met Glu Asp Arg Leu Ala Glu Thr Ser Arg Ala Lys Asp 335 340 345 His His Ile Ser Gly Ala Glu Val Gly Lys Ala Ser Thr 350 355 12 358 PRT Homo sapiens misc_feature Incyte ID No 71678683CD1 12 Met Asp Asp Ala Thr Val Leu Arg Lys Lys Gly Tyr Ile Val Gly 1 5 10 15 Ile Asn Leu Gly Lys Gly Ser Tyr Ala Lys Val Lys Ser Ala Tyr 20 25 30 Ser Glu Arg Leu Lys Phe Asn Val Ala Val Lys Ile Ile Asp Arg 35 40 45 Lys Lys Thr Pro Thr Asp Phe Val Glu Arg Phe Leu Pro Arg Glu 50 55 60 Met Asp Ile Leu Ala Thr Val Asn His Gly Ser Ile Ile Lys Thr 65 70 75 Tyr Glu Ile Phe Glu Thr Ser Asp Gly Arg Ile Tyr Ile Ile Met 80 85 90 Glu Leu Gly Val Gln Gly Asp Leu Leu Glu Phe Ile Lys Cys Gln 95 100 105 Gly Ala Leu His Glu Asp Val Ala Arg Lys Met Phe Arg Gln Leu 110 115 120 Ser Ser Ala Val Lys Tyr Cys His Asp Leu Asp Ile Val His Arg 125 130 135 Asp Leu Lys Cys Glu Asn Leu Leu Leu Asp Lys Asp Phe Asn Ile 140 145 150 Lys Leu Ser Asp Phe Gly Phe Ser Lys Arg Cys Leu Arg Asp Ser 155 160 165 Asn Gly Arg Ile Ile Leu Ser Lys Thr Phe Cys Gly Ser Ala Ala 170 175 180 Tyr Ala Ala Pro Glu Val Leu Gln Ser Ile Pro Tyr Gln Pro Lys 185 190 195 Val Tyr Asp Ile Trp Ser Leu Gly Val Ile Leu Tyr Ile Met Val 200 205 210 Cys Gly Ser Met Pro Tyr Asp Asp Ser Asp Ile Arg Lys Met Leu 215 220 225 Arg Ile Gln Lys Glu His Arg Val Asp Phe Pro Arg Ser Lys Asn 230 235 240 Leu Thr Cys Glu Cys Lys Asp Leu Ile Tyr Arg Met Leu Gln Pro 245 250 255 Asp Val Ser Gln Arg Leu His Ile Asp Glu Ile Leu Ser His Ser 260 265 270 Trp Leu Gln Pro Pro Lys Pro Lys Ala Thr Ser Ser Ala Ser Phe 275 280 285 Lys Arg Glu Gly Glu Gly Lys Tyr Arg Ala Glu Cys Lys Leu Asp 290 295 300 Thr Lys Thr Gly Leu Arg Pro Asp His Arg Pro Asp His Lys Leu 305 310 315 Gly Ala Lys Thr Gln His Arg Leu Leu Val Val Pro Glu Asn Glu 320 325 330 Asn Arg Met Glu Asp Arg Leu Ala Glu Thr Ser Arg Ala Lys Asp 335 340 345 His His Ile Ser Gly Ala Glu Val Gly Lys Ala Ser Thr 350 355 13 929 PRT Homo sapiens misc_feature Incyte ID No 7474567CD1 13 Met Glu Ser Met Leu Asn Lys Leu Lys Ser Thr Val Thr Lys Val 1 5 10 15 Thr Ala Asp Val Thr Ser Ala Val Met Gly Asn Pro Val Thr Arg 20 25 30 Glu Phe Asp Val Gly Arg His Ile Ala Ser Gly Gly Asn Gly Leu 35 40 45 Ala Trp Lys Ile Phe Asn Gly Thr Lys Lys Ser Thr Lys Gln Glu 50 55 60 Val Ala Val Phe Val Phe Asp Lys Lys Leu Ile Asp Lys Tyr Gln 65 70 75 Lys Phe Glu Lys Asp Gln Ile Ile Asp Ser Leu Lys Arg Gly Val 80 85 90 Gln Gln Leu Thr Arg Leu Arg His Pro Arg Leu Leu Thr Val Gln 95 100 105 His Pro Leu Glu Glu Ser Arg Asp Cys Leu Ala Phe Cys Thr Glu 110 115 120 Pro Val Phe Ala Ser Leu Ala Asn Val Leu Gly Asn Trp Glu Asn 125 130 135 Leu Pro Ser Pro Ile Ser Pro Asp Ile Lys Asp Tyr Lys Leu Tyr 140 145 150 Asp Val Glu Thr Lys Tyr Gly Leu Leu Gln Val Ser Glu Gly Leu 155 160 165 Ser Phe Leu His Ser Ser Val Lys Met Val His Gly Asn Ile Thr 170 175 180 Pro Glu Asn Ile Ile Leu Asn Lys Ser Gly Ala Trp Lys Ile Met 185 190 195 Gly Phe Asp Phe Cys Val Ser Ser Thr Asn Pro Ser Glu Gln Glu 200 205 210 Pro Lys Phe Pro Cys Lys Glu Trp Asp Pro Asn Leu Pro Ser Leu 215 220 225 Cys Leu Pro Asn Pro Glu Tyr Leu Ala Pro Glu Tyr Ile Leu Ser 230 235 240 Val Ser Cys Glu Thr Ala Ser Asp Met Tyr Ser Leu Gly Thr Val 245 250 255 Met Tyr Ala Val Phe Asn Lys Gly Lys Pro Ile Phe Glu Val Asn 260 265 270 Lys Gln Asp Ile Tyr Lys Ser Phe Ser Arg Gln Leu Asp Gln Leu 275 280 285 Ser Arg Leu Gly Ser Ser Ser Leu Thr Asn Ile Pro Glu Glu Val 290 295 300 Arg Glu His Val Lys Leu Leu Leu Asn Val Thr Pro Thr Val Arg 305 310 315 Pro Asp Ala Asp Gln Met Thr Lys Ile Pro Phe Phe Asp Asp Val 320 325 330 Gly Ala Val Thr Leu Gln Tyr Phe Asp Thr Leu Phe Gln Arg Asp 335 340 345 Asn Leu Gln Lys Ser Gln Phe Phe Lys Gly Leu Pro Lys Val Leu 350 355 360 Pro Lys Leu Pro Lys Arg Val Ile Val Gln Arg Ile Leu Pro Cys 365 370 375 Leu Thr Ser Glu Phe Val Asn Pro Asp Met Val Pro Phe Val Leu 380 385 390 Pro Asn Val Leu Leu Ile Ala Glu Glu Cys Thr Lys Glu Glu Tyr 395 400 405 Val Lys Leu Ile Leu Pro Glu Leu Gly Pro Val Phe Lys Gln Gln 410 415 420 Glu Pro Ile Gln Ile Leu Leu Ile Phe Leu Gln Lys Met Asp Leu 425 430 435 Leu Leu Thr Lys Thr Pro Pro Asp Glu Ile Lys Asn Ser Val Leu 440 445 450 Pro Met Val Tyr Arg Ala Leu Glu Ala Pro Ser Ile Gln Ile Gln 455 460 465 Glu Leu Cys Leu Asn Ile Ile Pro Thr Phe Ala Asn Leu Ile Asp 470 475 480 Tyr Pro Ser Met Lys Asn Ala Leu Ile Pro Arg Ile Lys Asn Ala 485 490 495 Cys Leu Gln Thr Ser Ser Leu Ala Val Arg Val Asn Ser Leu Val 500 505 510 Cys Leu Gly Lys Ile Leu Glu Tyr Leu Asp Lys Trp Phe Val Leu 515 520 525 Asp Asp Ile Leu Pro Phe Leu Gln Gln Ile Pro Ser Lys Glu Pro 530 535 540 Ala Val Leu Met Gly Ile Leu Gly Ile Tyr Lys Cys Thr Phe Thr 545 550 555 His Lys Lys Leu Gly Ile Thr Lys Glu Gln Leu Ala Gly Lys Val 560 565 570 Leu Pro His Leu Ile Pro Leu Ser Ile Glu Asn Asn Leu Asn Leu 575 580 585 Asn Gln Phe Asn Ser Phe Ile Ser Val Ile Lys Glu Met Leu Asn 590 595 600 Arg Leu Glu Ser Glu His Lys Thr Lys Leu Glu Gln Leu His Ile 605 610 615 Met Gln Glu Gln Gln Lys Ser Leu Asp Ile Gly Asn Gln Met Asn 620 625 630 Val Ser Glu Glu Met Lys Val Thr Asn Ile Gly Asn Gln Gln Ile 635 640 645 Asp Lys Val Phe Asn Asn Ile Gly Ala Asp Leu Leu Thr Gly Ser 650 655 660 Glu Ser Glu Asn Lys Glu Asp Gly Leu Gln Asn Lys His Lys Arg 665 670 675 Ala Ser Leu Thr Leu Glu Glu Lys Gln Lys Leu Ala Lys Glu Gln 680 685 690 Glu Gln Ala Gln Lys Leu Lys Ser Gln Gln Pro Leu Lys Pro Gln 695 700 705 Val His Thr Pro Val Ala Thr Val Lys Gln Thr Lys Asp Leu Thr 710 715 720 Asp Thr Leu Met Asp Asn Met Ser Ser Leu Thr Ser Leu Ser Val 725 730 735 Ser Thr Pro Lys Ser Ser Ala Ser Ser Thr Phe Thr Ser Val Pro 740 745 750 Ser Met Gly Ile Gly Met Met Phe Ser Thr Pro Thr Asp Asn Thr 755 760 765 Lys Arg Asn Leu Thr Asn Gly Leu Asn Ala Asn Met Gly Phe Gln 770 775 780 Thr Ser Gly Phe Asn Met Pro Val Asn Thr Asn Gln Asn Phe Tyr 785 790 795 Ser Ser Pro Ser Thr Val Gly Val Thr Lys Met Thr Leu Gly Thr 800 805 810 Pro Pro Thr Leu Pro Asn Phe Asn Ala Leu Ser Val Pro Pro Ala 815 820 825 Gly Ala Lys Gln Thr Gln Gln Arg Pro Thr Asp Met Ser Ala Leu 830 835 840 Asn Asn Leu Phe Gly Pro Gln Lys Pro Lys Val Ser Met Asn Gln 845 850 855 Leu Ser Gln Gln Lys Pro Asn Gln Trp Leu Asn Gln Phe Val Pro 860 865 870 Pro Gln Gly Ser Pro Thr Met Gly Ser Ser Val Met Gly Thr Gln 875 880 885 Met Asn Val Ile Gly Gln Ser Ala Phe Gly Met Gln Gly Asn Pro 890 895 900 Phe Phe Asn Pro Gln Asn Phe Ala Gln Pro Pro Thr Thr Met Thr 905 910 915 Asn Ser Ser Ser Ala Ser Asn Asp Leu Lys Asp Leu Phe Gly 920 925 14 523 PRT Homo sapiens misc_feature Incyte ID No 3838946CD1 14 Met Ala Ala Ala Leu Gln Val Leu Pro Arg Leu Ala Arg Ala Pro 1 5 10 15 Leu His Pro Leu Leu Trp Arg Gly Ser Val Ala Arg Leu Ala Ser 20 25 30 Ser Met Ala Leu Ala Glu Gln Ala Arg Gln Leu Phe Glu Ser Ala 35 40 45 Val Gly Ala Val Leu Pro Gly Pro Met Leu His Arg Ala Leu Ser 50 55 60 Leu Asp Pro Gly Gly Arg Gln Leu Lys Val Arg Asp Arg Asn Phe 65 70 75 Gln Leu Arg Gln Asn Leu Tyr Leu Val Gly Phe Gly Lys Ala Val 80 85 90 Leu Gly Met Ala Ala Ala Ala Glu Glu Leu Leu Gly Gln His Leu 95 100 105 Val Gln Gly Val Ile Ser Val Pro Lys Gly Ile Arg Ala Ala Met 110 115 120 Glu Arg Ala Gly Lys Gln Glu Met Leu Leu Lys Pro His Ser Arg 125 130 135 Val Gln Val Phe Glu Gly Ala Glu Asp Asn Leu Pro Asp Arg Asp 140 145 150 Ala Leu Arg Ala Ala Leu Ala Ile Gln Gln Leu Ala Glu Gly Leu 155 160 165 Thr Ala Asp Asp Leu Leu Leu Val Leu Ile Ser Gly Gly Gly Ser 170 175 180 Ala Leu Leu Pro Ala Pro Ile Pro Pro Val Thr Leu Glu Glu Lys 185 190 195 Gln Thr Leu Thr Arg Leu Leu Ala Ala Arg Gly Ala Thr Ile Gln 200 205 210 Glu Leu Asn Thr Ile Arg Lys Ala Leu Ser Gln Leu Lys Gly Gly 215 220 225 Gly Leu Ala Gln Ala Ala Tyr Pro Ala Gln Val Val Ser Leu Ile 230 235 240 Leu Ser Asp Val Val Gly Asp Pro Val Glu Val Ile Ala Ser Gly 245 250 255 Pro Thr Val Ala Ser Ser His Asn Val Gln Asp Cys Leu His Ile 260 265 270 Leu Asn Arg Tyr Gly Leu Arg Ala Ala Leu Pro Arg Ser Val Lys 275 280 285 Thr Val Leu Ser Arg Ala Asp Ser Asp Pro His Gly Pro His Thr 290 295 300 Cys Gly His Val Leu Asn Val Ile Ile Gly Ser Asn Val Leu Ala 305 310 315 Leu Ala Glu Ala Gln Arg Gln Ala Glu Ala Leu Gly Tyr Gln Ala 320 325 330 Val Val Leu Ser Ala Ala Met Gln Gly Asp Val Lys Ser Met Ala 335 340 345 Gln Phe Tyr Gly Leu Leu Ala His Val Ala Arg Thr Arg Leu Thr 350 355 360 Pro Ser Met Ala Gly Ala Ser Val Glu Glu Asp Ala Gln Leu His 365 370 375 Glu Leu Ala Ala Glu Leu Gln Ile Pro Asp Leu Gln Leu Glu Glu 380 385 390 Ala Leu Glu Thr Met Ala Trp Gly Arg Gly Pro Val Cys Leu Leu 395 400 405 Ala Gly Gly Glu Pro Thr Val Gln Leu Gln Gly Ser Gly Arg Gly 410 415 420 Gly Arg Asn Gln Glu Leu Ala Leu Arg Val Gly Ala Glu Leu Arg 425 430 435 Arg Trp Pro Leu Gly Pro Ile Asp Val Leu Phe Leu Ser Gly Gly 440 445 450 Thr Asp Gly Gln Asp Gly Pro Thr Glu Ala Ala Gly Ala Trp Val 455 460 465 Thr Pro Glu Leu Ala Ser Gln Ala Ala Ala Glu Gly Leu Asp Ile 470 475 480 Ala Thr Phe Leu Ala His Asn Asp Ser His Thr Phe Phe Cys Cys 485 490 495 Leu Gln Gly Gly Ala His Leu Leu His Thr Gly Met Thr Gly Thr 500 505 510 Asn Val Met Asp Thr His Leu Leu Phe Leu Arg Pro Arg 515 520 15 459 PRT Homo sapiens misc_feature Incyte ID No 72001176CD1 15 Met Asp His Pro Ser Arg Glu Lys Asp Glu Arg Gln Arg Thr Thr 1 5 10 15 Lys Pro Met Ala Gln Arg Ser Ala His Cys Ser Arg Pro Ser Gly 20 25 30 Ser Ser Ser Ser Ser Gly Val Leu Met Val Gly Pro Asn Phe Arg 35 40 45 Val Gly Lys Lys Ile Gly Cys Gly Asn Phe Gly Glu Leu Arg Leu 50 55 60 Gly Lys Asn Leu Tyr Thr Asn Glu Tyr Val Ala Ile Lys Leu Glu 65 70 75 Pro Ile Lys Ser Arg Ala Leu Gln Leu His Leu Glu Tyr Arg Phe 80 85 90 Tyr Lys Gln Leu Gly Ser Ala Gly Glu Gly Leu Pro Gln Val Tyr 95 100 105 Tyr Phe Gly Pro Cys Gly Lys Tyr Asn Ala Met Val Leu Glu Leu 110 115 120 Leu Gly Pro Ser Leu Glu Asp Leu Phe Asp Leu Cys Asp Arg Thr 125 130 135 Phe Thr Leu Lys Thr Val Leu Met Ile Ala Ile Gln Leu Leu Ser 140 145 150 Arg Met Glu Tyr Val His Ser Lys Asn Leu Ile Tyr Arg Asp Val 155 160 165 Lys Pro Glu Asn Phe Leu Ile Gly Arg Gln Gly Asn Lys Lys Glu 170 175 180 His Val Ile His Ile Ile Asp Phe Gly Leu Ala Lys Glu Tyr Ile 185 190 195 Asp Pro Glu Thr Lys Lys His Ile Pro Tyr Arg Glu His Lys Ser 200 205 210 Leu Thr Gly Thr Ala Arg Tyr Met Ser Ile Asn Thr His Leu Gly 215 220 225 Lys Glu Gln Ser Arg Arg Asp Asp Leu Glu Ala Leu Gly His Met 230 235 240 Phe Met Tyr Phe Leu Arg Gly Ser Leu Pro Trp Gln Gly Leu Lys 245 250 255 Ala Asp Thr Leu Lys Glu Arg Tyr Gln Lys Ile Gly Asp Thr Lys 260 265 270 Arg Asn Thr Pro Ile Glu Ala Leu Cys Glu Asn Phe Pro Glu Glu 275 280 285 Met Ala Thr Tyr Leu Arg Tyr Val Arg Arg Leu Asp Phe Phe Glu 290 295 300 Lys Pro Asp Tyr Glu Tyr Leu Arg Thr Leu Phe Thr Asp Leu Phe 305 310 315 Glu Lys Lys Gly Tyr Thr Phe Asp Tyr Ala Tyr Asp Trp Val Gly 320 325 330 Arg Pro Ile Pro Thr Pro Val Gly Ser Val His Val Asp Ser Gly 335 340 345 Ala Ser Ala Ile Thr Arg Glu Ser His Thr His Arg Asp Arg Pro 350 355 360 Ser Gln Gln Gln Pro Leu Arg Asn Gln Asn Val Ser Ser Glu Arg 365 370 375 Arg Gly Glu Trp Glu Ile Gln Pro Ser Arg Gln Thr Asn Thr Ser 380 385 390 Tyr Leu Thr Ser His Leu Ala Ala Asp Arg His Gly Gly Ser Val 395 400 405 Gln Val Val Ser Ser Thr Asn Gly Glu Leu Asn Val Asp Asp Pro 410 415 420 Thr Gly Ala His Ser Asn Ala Pro Ile Thr Ala His Ala Glu Val 425 430 435 Glu Val Val Glu Glu Ala Lys Cys Cys Cys Phe Phe Lys Arg Lys 440 445 450 Arg Lys Lys Thr Ala Gln Arg His Lys 455 16 1360 PRT Homo sapiens misc_feature Incyte ID No 55064363CD1 16 Met Lys Trp Val Gly Asp Thr Gly Val Gly Gly Asn Ile Pro Pro 1 5 10 15 Ser Phe Thr Thr Pro Gly Leu Ser Ser Arg Pro Gly Ala Met Val 20 25 30 Ala Asp Arg Ser Arg Trp Pro Leu Ala Gln Gly Lys Gly Ala Gln 35 40 45 Ala Gly Thr Trp Arg Ala Ala Val Glu Cys Ser Gly Arg Gly Leu 50 55 60 Gly Ala Ala Ser Glu Ser Pro Gln Cys Pro Pro Pro Pro Gly Val 65 70 75 Glu Gly Ala Ala Gly Pro Ala Glu Pro Asp Gly Ala Ala Glu Gly 80 85 90 Ala Ala Gly Gly Ser Gly Glu Gly Glu Ser Gly Gly Gly Pro Arg 95 100 105 Arg Ala Leu Arg Ala Val Tyr Val Arg Ser Glu Ser Ser Gln Gly 110 115 120 Gly Ala Ala Gly Gly Pro Glu Ala Gly Ala Arg Gln Cys Leu Leu 125 130 135 Arg Ala Cys Glu Ala Glu Gly Ala His Leu Thr Ser Val Pro Phe 140 145 150 Gly Glu Leu Asp Phe Gly Glu Thr Ala Val Leu Asp Ala Phe Tyr 155 160 165 Asp Ala Asp Val Ala Val Val Asp Met Ser Asp Val Ser Arg Gln 170 175 180 Pro Ser Leu Phe Tyr His Leu Gly Val Arg Glu Ser Phe Asp Met 185 190 195 Ala Asn Asn Val Ile Leu Tyr His Asp Thr Asp Ala Asp Thr Ala 200 205 210 Leu Ser Leu Lys Asp Met Val Thr Gln Lys Asn Thr Ala Ser Ser 215 220 225 Gly Asn Tyr Tyr Phe Ile Pro Tyr Ile Val Thr Pro Cys Thr Asp 230 235 240 Tyr Phe Cys Cys Glu Ser Asp Ala Gln Arg Arg Ala Ser Glu Tyr 245 250 255 Met Gln Pro Asn Trp Asp Asn Ile Leu Gly Pro Leu Cys Met Pro 260 265 270 Leu Val Asp Arg Phe Ile Ser Leu Leu Lys Asp Ile His Val Thr 275 280 285 Ser Cys Val Tyr Tyr Lys Glu Thr Leu Leu Asn Asp Ile Arg Lys 290 295 300 Ala Arg Glu Lys Tyr Gln Gly Glu Glu Leu Ala Lys Glu Leu Ala 305 310 315 Arg Ile Lys Leu Arg Met Asp Asn Thr Glu Val Leu Thr Ser Asp 320 325 330 Ile Ile Ile Asn Leu Leu Leu Ser Tyr Arg Asp Ile Gln Asp Tyr 335 340 345 Asp Ala Met Val Lys Leu Val Glu Thr Leu Glu Met Leu Pro Thr 350 355 360 Cys Asp Leu Ala Asp Gln His Asn Ile Lys Phe His Tyr Ala Phe 365 370 375 Ala Leu Asn Arg Arg Asn Ser Thr Gly Asp Arg Glu Lys Ala Leu 380 385 390 Gln Ile Met Leu Gln Val Leu Gln Ser Cys Asp His Pro Gly Pro 395 400 405 Asp Met Phe Cys Leu Cys Gly Arg Ile Tyr Lys Asp Ile Phe Leu 410 415 420 Asp Ser Asp Cys Lys Asp Asp Thr Ser Arg Asp Ser Ala Ile Glu 425 430 435 Trp Tyr Arg Lys Gly Phe Glu Leu Gln Ser Ser Leu Tyr Ser Gly 440 445 450 Ile Asn Leu Ala Val Leu Leu Ile Val Ala Gly Gln Gln Phe Glu 455 460 465 Thr Ser Leu Glu Leu Arg Lys Ile Gly Val Arg Leu Asn Ser Leu 470 475 480 Leu Gly Arg Lys Gly Ser Leu Glu Lys Met Asn Asn Tyr Trp Asp 485 490 495 Val Gly Gln Phe Phe Ser Val Ser Met Leu Ala His Asp Val Gly 500 505 510 Lys Ala Val Gln Ala Ala Glu Arg Leu Phe Lys Leu Lys Pro Pro 515 520 525 Val Trp Tyr Leu Arg Ser Leu Val Gln Asn Leu Leu Leu Ile Arg 530 535 540 Arg Phe Lys Lys Thr Ile Ile Glu His Ser Pro Arg Gln Glu Arg 545 550 555 Leu Asn Phe Trp Leu Asp Ile Ile Phe Glu Ala Thr Asn Glu Val 560 565 570 Thr Asn Gly Leu Arg Phe Pro Val Leu Val Ile Glu Pro Thr Lys 575 580 585 Val Tyr Gln Pro Ser Tyr Val Ser Ile Asn Asn Glu Ala Glu Glu 590 595 600 Arg Thr Val Ser Leu Trp His Val Ser Pro Thr Glu Met Lys Gln 605 610 615 Met His Glu Trp Asn Phe Thr Ala Ser Ser Ile Lys Gly Ile Ser 620 625 630 Leu Ser Lys Phe Asp Glu Arg Cys Cys Phe Leu Tyr Val His Asp 635 640 645 Asn Ser Asp Asp Phe Gln Ile Tyr Phe Ser Thr Glu Glu Gln Cys 650 655 660 Ser Arg Phe Phe Ser Leu Val Lys Glu Met Ile Thr Asn Thr Ala 665 670 675 Gly Ser Thr Val Glu Leu Glu Gly Glu Thr Asp Gly Asp Thr Leu 680 685 690 Glu Tyr Glu Tyr Asp His Asp Ala Asn Gly Glu Arg Val Val Leu 695 700 705 Gly Lys Gly Thr Tyr Gly Ile Val Tyr Ala Gly Arg Asp Leu Ser 710 715 720 Asn Gln Val Arg Ile Ala Ile Lys Glu Ile Pro Glu Arg Asp Ser 725 730 735 Arg Tyr Ser Gln Pro Leu His Glu Glu Ile Ala Leu His Lys Tyr 740 745 750 Leu Lys His Arg Asn Ile Val Gln Tyr Leu Gly Ser Val Ser Glu 755 760 765 Asn Gly Tyr Ile Lys Ile Phe Met Glu Gln Val Pro Gly Gly Ser 770 775 780 Leu Ser Ala Leu Leu Arg Ser Lys Trp Gly Pro Met Lys Glu Pro 785 790 795 Thr Ile Lys Phe Tyr Thr Lys Gln Ile Leu Glu Gly Leu Lys Tyr 800 805 810 Leu His Glu Asn Gln Ile Val His Arg Asp Ile Lys Gly Asp Asn 815 820 825 Val Leu Val Asn Thr Tyr Ser Gly Val Val Lys Ile Ser Asp Phe 830 835 840 Gly Thr Ser Lys Arg Leu Ala Gly Val Asn Pro Cys Thr Glu Thr 845 850 855 Phe Thr Gly Thr Leu Gln Tyr Met Ala Pro Glu Ile Ile Asp Gln 860 865 870 Gly Pro Arg Gly Tyr Gly Ala Pro Ala Asp Ile Trp Ser Leu Gly 875 880 885 Cys Thr Ile Ile Glu Met Ala Thr Ser Lys Pro Pro Phe His Glu 890 895 900 Leu Gly Glu Pro Gln Ala Ala Met Phe Lys Val Gly Met Phe Lys 905 910 915 Ile His Pro Glu Ile Pro Glu Ala Leu Ser Ala Glu Ala Arg Ala 920 925 930 Phe Ile Leu Ser Cys Phe Glu Pro Asp Pro His Lys Arg Ala Thr 935 940 945 Thr Ala Glu Leu Leu Arg Glu Gly Phe Leu Arg Gln Val Asn Lys 950 955 960 Gly Lys Lys Asn Arg Ile Ala Phe Lys Pro Ser Glu Gly Pro Arg 965 970 975 Gly Val Val Leu Ala Leu Pro Thr Gln Gly Glu Pro Met Ala Thr 980 985 990 Ser Ser Ser Glu His Gly Ser Val Ser Pro Asp Ser Asp Ala Gln 995 1000 1005 Pro Asp Ala Leu Phe Glu Arg Thr Arg Ala Pro Arg His His Leu 1010 1015 1020 Gly His Leu Leu Ser Val Pro Asp Glu Ser Ser Ala Leu Glu Asp 1025 1030 1035 Arg Gly Leu Ala Ser Ser Pro Glu Asp Arg Asp Gln Gly Leu Phe 1040 1045 1050 Leu Leu Arg Lys Asp Ser Glu Arg Arg Ala Ile Leu Tyr Lys Ile 1055 1060 1065 Leu Trp Glu Glu Gln Asn Gln Val Ala Ser Asn Leu Gln Glu Cys 1070 1075 1080 Val Ala Gln Ser Ser Glu Glu Leu His Leu Ser Val Gly His Ile 1085 1090 1095 Lys Gln Ile Ile Gly Ile Leu Arg Asp Phe Ile Arg Ser Pro Glu 1100 1105 1110 His Arg Val Met Ala Thr Thr Ile Ser Lys Leu Lys Val Asp Leu 1115 1120 1125 Asp Phe Asp Ser Ser Ser Ile Ser Gln Ile His Leu Val Leu Phe 1130 1135 1140 Gly Phe Gln Asp Ala Val Asn Lys Ile Leu Arg Asn His Leu Ile 1145 1150 1155 Arg Pro His Trp Met Phe Ala Met Asp Asn Ile Ile Arg Arg Ala 1160 1165 1170 Val Gln Ala Ala Val Thr Ile Leu Ile Pro Glu Leu Arg Ala His 1175 1180 1185 Phe Glu Pro Thr Cys Glu Thr Glu Gly Val Asp Lys Asp Met Asp 1190 1195 1200 Glu Ala Glu Glu Gly Tyr Pro Pro Ala Thr Gly Pro Gly Gln Glu 1205 1210 1215 Ala Gln Pro His Gln Gln His Leu Ser Leu Gln Leu Gly Glu Leu 1220 1225 1230 Arg Gln Glu Thr Asn Arg Leu Leu Glu His Leu Val Glu Lys Glu 1235 1240 1245 Arg Glu Tyr Gln Asn Leu Leu Arg Gln Thr Leu Glu Gln Lys Thr 1250 1255 1260 Gln Glu Leu Tyr His Leu Gln Leu Lys Leu Lys Ser Asn Cys Ile 1265 1270 1275 Thr Glu Asn Pro Ala Gly Pro Tyr Gly Gln Arg Thr Asp Lys Glu 1280 1285 1290 Leu Ile Asp Trp Leu Arg Leu Gln Gly Ala Asp Ala Lys Thr Ile 1295 1300 1305 Glu Lys Ile Val Glu Glu Gly Tyr Thr Leu Ser Asp Ile Leu Asn 1310 1315 1320 Glu Ile Thr Lys Glu Asp Leu Arg Tyr Leu Arg Leu Arg Gly Gly 1325 1330 1335 Leu Leu Cys Arg Leu Trp Ser Ala Val Ser Gln Tyr Arg Arg Ala 1340 1345 1350 Gln Glu Ala Ser Glu Thr Lys Asp Lys Ala 1355 1360 17 1345 PRT Homo sapiens misc_feature Incyte ID No 7482044CD1 17 Met Glu Pro Gly Arg Gly Ala Gly Pro Ala Gly Met Ala Glu Pro 1 5 10 15 Arg Ala Lys Ala Ala Arg Pro Gly Pro Gln Arg Phe Leu Arg Arg 20 25 30 Ser Val Val Glu Ser Asp Gln Glu Glu Pro Pro Gly Leu Glu Ala 35 40 45 Ala Glu Ala Pro Gly Pro Gln Pro Pro Gln Pro Leu Gln Arg Arg 50 55 60 Val Leu Leu Leu Cys Lys Thr Arg Arg Leu Ile Ala Glu Arg Ala 65 70 75 Arg Gly Arg Pro Ala Ala Pro Ala Pro Ala Ala Leu Val Ala Gln 80 85 90 Pro Gly Ala Pro Gly Ala Pro Ala Asp Ala Gly Pro Glu Pro Val 95 100 105 Gly Thr Gln Glu Pro Gly Pro Asp Pro Ile Ala Ala Ala Val Glu 110 115 120 Thr Ala Pro Ala Pro Asp Gly Gly Pro Arg Glu Glu Ala Ala Ala 125 130 135 Thr Val Arg Lys Glu Asp Glu Gly Ala Ala Glu Ala Lys Pro Glu 140 145 150 Pro Gly Arg Thr Arg Arg Asp Glu Pro Glu Glu Glu Glu Asp Asp 155 160 165 Glu Asp Asp Leu Lys Ala Val Ala Thr Ser Leu Asp Gly Arg Phe 170 175 180 Leu Lys Phe Asp Ile Glu Leu Gly Arg Gly Ser Phe Lys Thr Val 185 190 195 Tyr Lys Gly Leu Asp Thr Glu Thr Trp Val Glu Val Ala Trp Cys 200 205 210 Glu Leu Gln Asp Arg Lys Leu Thr Lys Leu Glu Arg Gln Arg Phe 215 220 225 Lys Glu Glu Ala Glu Met Leu Lys Gly Leu Gln His Pro Asn Ile 230 235 240 Val Arg Phe Tyr Asp Phe Trp Glu Ser Ser Ala Lys Gly Lys Arg 245 250 255 Cys Ile Val Leu Val Thr Glu Leu Met Thr Ser Gly Thr Leu Lys 260 265 270 Thr Tyr Leu Lys Arg Phe Lys Val Met Lys Pro Lys Val Leu Arg 275 280 285 Ser Trp Cys Arg Gln Ile Leu Lys Gly Leu Leu Phe Leu His Thr 290 295 300 Arg Thr Pro Pro Ile Ile His Arg Asp Leu Lys Cys Asp Asn Ile 305 310 315 Phe Ile Thr Gly Pro Thr Gly Ser Val Lys Ile Gly Asp Leu Gly 320 325 330 Leu Ala Thr Leu Lys Arg Ala Ser Phe Ala Lys Ser Val Ile Gly 335 340 345 Thr Pro Glu Phe Met Ala Pro Glu Met Tyr Glu Glu His Tyr Asp 350 355 360 Glu Ser Val Asp Val Tyr Ala Phe Gly Met Cys Met Leu Glu Met 365 370 375 Ala Thr Ser Glu Tyr Pro Tyr Ser Glu Cys Gln Asn Ala Ala Gln 380 385 390 Ile Tyr Arg Lys Val Thr Cys Gly Ile Lys Pro Ala Ser Phe Glu 395 400 405 Lys Val His Asp Pro Glu Ile Lys Glu Ile Ile Gly Glu Cys Ile 410 415 420 Cys Lys Asn Lys Glu Glu Arg Tyr Glu Ile Lys Asp Leu Leu Ser 425 430 435 His Ala Phe Phe Ala Glu Asp Thr Gly Val Arg Val Glu Leu Ala 440 445 450 Glu Glu Asp His Gly Arg Lys Ser Thr Ile Ala Leu Arg Leu Trp 455 460 465 Val Glu Asp Pro Lys Lys Leu Lys Gly Lys Pro Lys Asp Asn Gly 470 475 480 Ala Ile Glu Phe Thr Phe Asp Leu Glu Lys Glu Thr Pro Asp Glu 485 490 495 Val Ala Gln Glu Met Ile Glu Ser Gly Phe Phe His Glu Ser Asp 500 505 510 Val Lys Ile Val Ala Lys Ser Ile Arg Asp Arg Val Ala Leu Ile 515 520 525 Gln Trp Arg Arg Glu Arg Ile Trp Pro Ala Leu Gln Pro Lys Glu 530 535 540 Gln Gln Asp Val Gly Ser Pro Asp Lys Ala Arg Gly Pro Pro Val 545 550 555 Pro Leu Gln Val Gln Val Thr Tyr His Ala Gln Ala Gly Gln Pro 560 565 570 Gly Pro Pro Glu Pro Glu Glu Pro Glu Ala Asp Gln His Leu Leu 575 580 585 Pro Pro Thr Leu Pro Thr Ser Ala Thr Ser Leu Ala Ser Asp Ser 590 595 600 Thr Phe Asp Ser Gly Gln Gly Ser Thr Val Tyr Ser Asp Ser Gln 605 610 615 Ser Ser Gln Gln Ser Val Met Leu Gly Ser Leu Ala Asp Ala Ala 620 625 630 Pro Ser Pro Ala Gln Cys Val Cys Ser Pro Pro Val Ser Glu Gly 635 640 645 Pro Val Leu Pro Gln Ser Leu Pro Ser Leu Gly Ala Tyr Gln Gln 650 655 660 Pro Thr Ala Ala Pro Gly Leu Pro Val Gly Ser Val Pro Ala Pro 665 670 675 Ala Cys Pro Pro Ser Leu Gln Gln His Phe Pro Asp Pro Ala Met 680 685 690 Ser Phe Ala Pro Val Leu Pro Pro Pro Ser Thr Pro Met Pro Thr 695 700 705 Gly Pro Gly Gln Pro Ala Pro Pro Gly Gln Gln Pro Pro Pro Leu 710 715 720 Ala Gln Pro Thr Pro Leu Pro Gln Val Leu Ala Pro Gln Pro Val 725 730 735 Val Pro Leu Gln Pro Val Pro Pro His Leu Pro Pro Tyr Leu Ala 740 745 750 Pro Ala Ser Gln Val Gly Ala Pro Ala Gln Leu Lys Pro Leu Gln 755 760 765 Met Pro Gln Ala Pro Leu Gln Pro Leu Ala Gln Val Pro Pro Gln 770 775 780 Met Pro Pro Ile Pro Val Val Pro Pro Ile Thr Pro Leu Ala Gly 785 790 795 Ile Asp Gly Leu Pro Pro Ala Leu Pro Asp Leu Pro Thr Ala Thr 800 805 810 Val Pro Pro Met Pro Pro Pro Gln Tyr Phe Ser Pro Ala Val Ile 815 820 825 Leu Pro Ser Leu Ala Ala Pro Leu Pro Pro Ala Ser Pro Ala Leu 830 835 840 Pro Leu Gln Ala Val Lys Leu Pro His Pro Pro Gly Ala Pro Leu 845 850 855 Ala Met Pro Cys Arg Thr Ile Val Pro Asn Ala Pro Ala Thr Ile 860 865 870 Pro Leu Leu Ala Val Ala Pro Pro Gly Val Ala Ala Leu Ser Ile 875 880 885 His Ser Ala Val Ala Gln Leu Pro Gly Gln Pro Val Tyr Pro Ala 890 895 900 Ala Phe Pro Gln Met Ala Pro Thr Asp Val Pro Pro Ser Pro His 905 910 915 His Thr Val Gln Asn Met Arg Ala Thr Pro Pro Gln Pro Ala Leu 920 925 930 Pro Pro Gln Pro Thr Leu Pro Pro Gln Pro Val Leu Pro Pro Gln 935 940 945 Pro Thr Leu Pro Pro Gln Pro Val Leu Pro Pro Gln Pro Thr Arg 950 955 960 Pro Pro Gln Pro Val Leu Pro Pro Gln Pro Met Leu Pro Pro Gln 965 970 975 Pro Val Leu Pro Pro Gln Pro Ala Leu Pro Val Arg Pro Glu Pro 980 985 990 Leu Gln Pro His Leu Pro Glu Gln Ala Ala Pro Ala Ala Thr Pro 995 1000 1005 Gly Ser Gln Ile Leu Leu Gly His Pro Ala Pro Tyr Ala Val Asp 1010 1015 1020 Val Ala Ala Gln Val Pro Thr Val Pro Val Pro Pro Ala Ala Val 1025 1030 1035 Leu Ser Pro Pro Leu Pro Glu Val Leu Leu Pro Ala Ala Pro Glu 1040 1045 1050 Leu Leu Pro Gln Phe Pro Ser Ser Leu Ala Thr Val Ser Ala Ser 1055 1060 1065 Val Gln Ser Val Pro Thr Gln Thr Ala Thr Leu Leu Pro Pro Ala 1070 1075 1080 Asn Pro Pro Leu Pro Gly Gly Pro Gly Ile Ala Ser Pro Cys Pro 1085 1090 1095 Thr Val Gln Leu Thr Val Glu Pro Val Gln Glu Glu Gln Ala Ser 1100 1105 1110 Gln Asp Lys Pro Pro Gly Leu Pro Gln Ser Cys Glu Ser Tyr Gly 1115 1120 1125 Gly Ser Asp Val Thr Ser Gly Lys Glu Leu Ser Asp Ser Cys Glu 1130 1135 1140 Gly Ala Phe Gly Gly Gly Arg Leu Glu Gly Arg Ala Ala Arg Lys 1145 1150 1155 His His Arg Arg Ser Thr Arg Ala Arg Ser Arg Gln Glu Arg Ala 1160 1165 1170 Ser Arg Pro Arg Leu Thr Ile Leu Asn Val Cys Asn Thr Gly Asp 1175 1180 1185 Lys Met Val Glu Cys Gln Leu Glu Thr His Asn His Lys Met Val 1190 1195 1200 Thr Phe Lys Phe Asp Leu Asp Gly Asp Ala Pro Asp Glu Ile Ala 1205 1210 1215 Thr Tyr Met Val Glu His Asp Phe Ile Leu Gln Ala Glu Arg Glu 1220 1225 1230 Thr Phe Ile Glu Gln Met Lys Asp Val Met Asp Lys Ala Glu Asp 1235 1240 1245 Met Leu Ser Glu Asp Thr Asp Ala Asp Arg Gly Ser Asp Pro Gly 1250 1255 1260 Thr Ser Pro Pro His Leu Ser Thr Cys Gly Leu Gly Thr Gly Glu 1265 1270 1275 Glu Ser Arg Gln Ser Gln Ala Asn Ala Pro Val Tyr Gln Gln Asn 1280 1285 1290 Val Leu His Thr Gly Lys Arg Trp Phe Ile Ile Cys Pro Val Ala 1295 1300 1305 Glu His Pro Ala Pro Glu Ala Pro Glu Ser Ser Pro Pro Leu Pro 1310 1315 1320 Leu Ser Ser Leu Pro Cys Pro Ala Leu Phe Arg Met Ser Cys Ala 1325 1330 1335 Ser Val Leu Ala Cys Pro Leu Ser Ala Cys 1340 1345 18 2038 PRT Homo sapiens misc_feature Incyte ID No 7476595CD1 18 Met Thr Ala Glu Thr Pro Glu Thr Asp Glu Ser Val Ser Ser Ser 1 5 10 15 Asn Ala Ser Leu Lys Leu Arg Arg Lys Pro Arg Glu Ser Asp Phe 20 25 30 Glu Thr Ile Lys Leu Ile Ser Asn Gly Ala Tyr Gly Ala Val Tyr 35 40 45 Phe Val Arg His Lys Glu Ser Arg Gln Arg Phe Ala Met Lys Lys 50 55 60 Ile Asn Lys Gln Asn Leu Ile Leu Arg Asn Gln Ile Gln Gln Ala 65 70 75 Phe Val Glu Arg Asp Ile Leu Thr Phe Ala Glu Asn Pro Phe Val 80 85 90 Val Ser Met Tyr Cys Ser Phe Glu Thr Arg Arg His Leu Cys Met 95 100 105 Val Met Glu Tyr Val Glu Gly Gly Asp Cys Ala Thr Leu Met Lys 110 115 120 Asn Met Gly Pro Leu Pro Val Asp Met Ala Arg Met Tyr Phe Ala 125 130 135 Glu Thr Val Leu Ala Leu Glu Tyr Leu His Asn Tyr Gly Ile Val 140 145 150 His Arg Asp Leu Lys Pro Asp Asn Leu Leu Val Thr Ser Met Gly 155 160 165 His Ile Lys Leu Thr Asp Phe Gly Leu Ser Lys Val Gly Leu Met 170 175 180 Ser Met Thr Thr Asn Leu Tyr Glu Gly His Ile Glu Lys Asp Ala 185 190 195 Arg Glu Phe Leu Asp Lys Gln Val Cys Gly Thr Pro Glu Tyr Ile 200 205 210 Ala Pro Glu Val Ile Leu Arg Gln Gly Tyr Gly Lys Pro Val Asp 215 220 225 Trp Trp Ala Met Gly Ile Ile Leu Tyr Glu Phe Leu Val Gly Cys 230 235 240 Val Pro Phe Phe Gly Asp Thr Pro Glu Glu Leu Phe Gly Gln Val 245 250 255 Ile Ser Asp Glu Ile Asn Trp Pro Glu Lys Asp Glu Ala Pro Pro 260 265 270 Pro Asp Ala Gln Asp Leu Ile Thr Leu Leu Leu Arg Gln Asn Pro 275 280 285 Leu Glu Arg Leu Gly Thr Gly Gly Ala Tyr Glu Val Lys Gln His 290 295 300 Arg Phe Phe Arg Ser Leu Asp Trp Asn Ser Leu Leu Arg Gln Lys 305 310 315 Ala Glu Phe Ile Pro Gln Leu Glu Ser Glu Asp Asp Thr Ser Tyr 320 325 330 Phe Asp Thr Arg Ser Glu Lys Tyr His His Met Glu Thr Glu Glu 335 340 345 Glu Asp Asp Thr Asn Asp Glu Asp Phe Asn Val Glu Ile Arg Gln 350 355 360 Phe Ser Ser Cys Ser His Arg Phe Ser Lys Leu Phe Leu Asn Asp 365 370 375 Tyr Leu Asp Ala Pro Ala Asn Gly Pro Ala Leu Pro Ser Cys Val 380 385 390 Trp Glu Trp His Arg Gly Lys Asp Phe Pro Gly Glu Gly Gly Ser 395 400 405 Gln Ser Val Leu Glu Pro Gly Gln Lys Leu Ala Lys Cys Gly Leu 410 415 420 Arg Pro Gly Leu Phe Ser Gly Pro Ser Lys Thr Thr Met Pro Thr 425 430 435 Pro Lys His Cys Phe Leu Leu Cys Leu Asp Thr Glu Ser Asn Arg 440 445 450 His Lys Leu Ser Ser Gly Leu Leu Pro Lys Leu Ala Ile Ser Thr 455 460 465 Glu Gly Glu Gln Asp Glu Ala Ala Ser Cys Pro Gly Asp Pro His 470 475 480 Glu Glu Pro Gly Lys Pro Ala Leu Pro Pro Glu Glu Cys Ala Gln 485 490 495 Glu Glu Pro Glu Val Thr Thr Pro Ala Ser Thr Ile Ser Ser Ser 500 505 510 Thr Leu Ser Asp Met Phe Ala Val Ser Pro Leu Gly Ser Pro Met 515 520 525 Ser Pro His Ser Leu Ser Ser Asp Pro Ser Ser Ser Arg Asp Ser 530 535 540 Ser Pro Ser Arg Asp Ser Ser Ala Ala Ser Ala Ser Pro His Gln 545 550 555 Pro Ile Val Ile His Ser Ser Gly Lys Asn Tyr Gly Phe Thr Ile 560 565 570 Arg Ala Ile Arg Val Tyr Val Gly Asp Ser Asp Ile Tyr Thr Val 575 580 585 His His Ile Val Trp Asn Val Glu Glu Gly Ser Pro Ala Cys Gln 590 595 600 Ala Gly Leu Lys Ala Gly Asp Leu Ile Thr His Ile Asn Gly Glu 605 610 615 Pro Val His Gly Leu Val His Thr Glu Val Ile Glu Leu Leu Leu 620 625 630 Lys Ser Gly Asn Lys Val Ser Ile Thr Thr Thr Pro Phe Glu Asn 635 640 645 Thr Ser Ile Lys Thr Gly Pro Ala Arg Arg Asn Ser Tyr Lys Ser 650 655 660 Arg Met Val Arg Arg Ser Lys Lys Ser Lys Lys Lys Glu Ser Leu 665 670 675 Glu Arg Arg Arg Ser Leu Phe Lys Lys Leu Ala Lys Gln Pro Ser 680 685 690 Pro Leu Leu His Thr Ser Arg Ser Phe Ser Cys Leu Asn Arg Ser 695 700 705 Leu Ser Ser Gly Glu Ser Leu Pro Gly Ser Pro Thr His Ser Leu 710 715 720 Ser Pro Arg Ser Pro Thr Pro Ser Tyr Arg Ser Thr Pro Asp Phe 725 730 735 Pro Ser Gly Thr Asn Ser Ser Gln Ser Ser Ser Pro Ser Ser Ser 740 745 750 Ala Pro Asn Ser Pro Ala Gly Ser Gly His Ile Arg Pro Ser Thr 755 760 765 Leu His Gly Leu Ala Pro Lys Leu Gly Gly Gln Arg Tyr Arg Ser 770 775 780 Gly Arg Arg Lys Ser Ala Gly Asn Ile Pro Leu Ser Pro Leu Ala 785 790 795 Arg Thr Pro Ser Pro Thr Pro Gln Pro Thr Ser Pro Gln Arg Ser 800 805 810 Pro Ser Pro Leu Leu Gly His Ser Leu Gly Asn Ser Lys Ile Ala 815 820 825 Gln Ala Phe Pro Ser Lys Met His Ser Pro Pro Thr Ile Val Arg 830 835 840 His Ile Val Arg Pro Lys Ser Ala Glu Pro Pro Arg Ser Pro Leu 845 850 855 Leu Lys Arg Val Gln Ser Glu Glu Lys Leu Ser Pro Ser Tyr Gly 860 865 870 Ser Asp Lys Lys His Leu Cys Ser Arg Lys His Ser Leu Glu Val 875 880 885 Thr Gln Glu Glu Val Gln Arg Glu Gln Ser Gln Arg Glu Ala Pro 890 895 900 Leu Gln Ser Leu Asp Glu Asn Val Cys Asp Val Pro Pro Leu Ser 905 910 915 Arg Ala Arg Pro Val Glu Gln Gly Cys Leu Lys Arg Pro Val Ser 920 925 930 Arg Lys Val Gly Arg Gln Glu Ser Val Asp Asp Leu Asp Arg Asp 935 940 945 Lys Leu Lys Ala Lys Val Val Val Lys Lys Ala Asp Gly Phe Pro 950 955 960 Glu Lys Gln Glu Ser His Gln Lys Ser His Gly Pro Gly Ser Asp 965 970 975 Leu Glu Asn Phe Ala Leu Phe Lys Leu Glu Glu Arg Glu Lys Lys 980 985 990 Val Tyr Pro Lys Ala Val Glu Arg Ser Ser Thr Phe Glu Asn Lys 995 1000 1005 Ala Ser Met Gln Glu Ala Pro Pro Leu Gly Ser Leu Leu Lys Asp 1010 1015 1020 Ala Leu His Lys Gln Ala Ser Val Arg Ala Ser Glu Gly Ala Met 1025 1030 1035 Ser Asp Gly Arg Val Pro Ala Glu His Arg Gln Gly Gly Gly Asp 1040 1045 1050 Phe Arg Arg Ala Pro Ala Pro Gly Thr Leu Gln Asp Gly Leu Cys 1055 1060 1065 His Ser Leu Asp Arg Gly Ile Ser Gly Lys Gly Glu Gly Thr Glu 1070 1075 1080 Lys Ser Ser Gln Ala Lys Glu Leu Leu Arg Cys Glu Lys Leu Asp 1085 1090 1095 Ser Lys Leu Ala Asn Ile Asp Tyr Leu Arg Lys Lys Met Ser Leu 1100 1105 1110 Glu Asp Lys Glu Asp Asn Leu Cys Pro Val Leu Lys Pro Lys Met 1115 1120 1125 Thr Ala Gly Ser His Glu Cys Leu Pro Gly Asn Pro Val Arg Pro 1130 1135 1140 Thr Gly Gly Gln Gln Glu Pro Pro Pro Ala Ser Glu Ser Arg Ala 1145 1150 1155 Phe Val Ser Ser Thr His Ala Ala Gln Met Ser Ala Val Ser Phe 1160 1165 1170 Val Pro Leu Lys Ala Leu Thr Gly Arg Val Asp Ser Gly Thr Glu 1175 1180 1185 Lys Pro Gly Leu Val Ala Pro Glu Ser Pro Val Arg Lys Ser Pro 1190 1195 1200 Ser Glu Tyr Lys Leu Glu Gly Arg Ser Val Ser Cys Leu Lys Pro 1205 1210 1215 Ile Glu Gly Thr Leu Asp Ile Ala Leu Leu Ser Gly Pro Gln Ala 1220 1225 1230 Ser Lys Thr Glu Leu Pro Ser Pro Glu Ser Ala Gln Ser Pro Ser 1235 1240 1245 Pro Ser Gly Asp Val Arg Ala Ser Val Pro Pro Val Leu Pro Ser 1250 1255 1260 Ser Ser Gly Lys Lys Asn Asp Thr Thr Ser Ala Arg Glu Leu Ser 1265 1270 1275 Pro Ser Ser Leu Lys Met Asn Lys Ser Tyr Leu Leu Glu Pro Trp 1280 1285 1290 Phe Leu Pro Pro Ser Arg Gly Leu Gln Asn Ser Pro Ala Val Ser 1295 1300 1305 Leu Pro Asp Pro Glu Phe Lys Arg Asp Arg Lys Gly Pro His Pro 1310 1315 1320 Thr Ala Arg Ser Pro Gly Thr Val Met Glu Ser Asn Pro Gln Gln 1325 1330 1335 Arg Glu Gly Ser Ser Pro Lys His Gln Asp His Thr Thr Asp Pro 1340 1345 1350 Lys Leu Leu Thr Cys Leu Gly Gln Asn Leu His Ser Pro Asp Leu 1355 1360 1365 Ala Arg Pro Arg Cys Pro Leu Pro Pro Glu Ala Ser Pro Ser Arg 1370 1375 1380 Glu Lys Pro Gly Leu Arg Glu Ser Ser Glu Arg Gly Pro Pro Thr 1385 1390 1395 Ala Arg Ser Glu Arg Ser Ala Ala Arg Ala Asp Thr Cys Arg Glu 1400 1405 1410 Pro Ser Met Glu Leu Cys Phe Pro Glu Thr Ala Lys Thr Ser Asp 1415 1420 1425 Asn Ser Lys Asn Leu Leu Ser Val Gly Arg Thr His Pro Asp Phe 1430 1435 1440 Tyr Thr Gln Thr Gln Ala Met Glu Lys Ala Trp Ala Pro Gly Gly 1445 1450 1455 Lys Thr Asn His Lys Asp Gly Pro Gly Glu Ala Arg Pro Pro Pro 1460 1465 1470 Arg Asp Asn Ser Ser Leu His Ser Ala Gly Ile Pro Cys Glu Lys 1475 1480 1485 Glu Leu Gly Lys Val Arg Arg Gly Val Glu Pro Lys Pro Glu Ala 1490 1495 1500 Leu Leu Ala Arg Arg Ser Leu Gln Pro Pro Gly Ile Glu Ser Glu 1505 1510 1515 Lys Ser Glu Lys Leu Ser Ser Phe Pro Ser Leu Gln Lys Asp Gly 1520 1525 1530 Ala Lys Glu Pro Glu Arg Lys Glu Gln Pro Leu Gln Arg His Pro 1535 1540 1545 Ser Ser Ile Pro Pro Pro Pro Leu Thr Ala Lys Asp Leu Ser Ser 1550 1555 1560 Pro Ala Ala Arg Gln His Cys Ser Ser Pro Ser His Ala Ser Gly 1565 1570 1575 Arg Glu Pro Gly Ala Lys Pro Ser Thr Ala Glu Pro Ser Ser Ser 1580 1585 1590 Pro Gln Asp Pro Pro Lys Pro Val Ala Ala His Ser Glu Ser Ser 1595 1600 1605 Ser His Lys Pro Arg Pro Gly Pro Asp Pro Gly Pro Pro Lys Thr 1610 1615 1620 Lys His Pro Asp Arg Ser Leu Ser Ser Gln Lys Pro Ser Val Gly 1625 1630 1635 Ala Thr Lys Gly Lys Glu Pro Ala Thr Gln Ser Leu Gly Gly Ser 1640 1645 1650 Ser Arg Glu Gly Lys Gly His Ser Lys Ser Gly Pro Asp Val Phe 1655 1660 1665 Pro Ala Thr Pro Gly Ser Gln Asn Lys Ala Ser Asp Gly Ile Gly 1670 1675 1680 Gln Gly Glu Gly Gly Pro Ser Val Pro Leu His Thr Asp Arg Ala 1685 1690 1695 Pro Leu Asp Ala Lys Pro Gln Pro Thr Ser Gly Gly Arg Pro Leu 1700 1705 1710 Glu Val Leu Glu Lys Pro Val His Leu Pro Arg Pro Gly His Pro 1715 1720 1725 Gly Pro Ser Glu Pro Ala Asp Gln Lys Leu Ser Ala Val Gly Glu 1730 1735 1740 Lys Gln Thr Leu Ser Pro Lys His Pro Lys Pro Ser Thr Val Lys 1745 1750 1755 Asp Cys Pro Thr Leu Cys Lys Gln Thr Asp Asn Arg Gln Thr Asp 1760 1765 1770 Lys Ser Pro Ser Gln Pro Ala Ala Asn Thr Asp Arg Arg Ala Glu 1775 1780 1785 Gly Lys Lys Cys Thr Glu Ala Leu Tyr Ala Pro Ala Glu Gly Asp 1790 1795 1800 Lys Leu Glu Ala Gly Leu Ser Phe Val His Ser Glu Asn Arg Leu 1805 1810 1815 Lys Gly Ala Glu Arg Pro Ala Ala Gly Val Gly Lys Gly Phe Pro 1820 1825 1830 Glu Ala Arg Gly Lys Gly Pro Gly Pro Gln Lys Pro Pro Thr Glu 1835 1840 1845 Ala Asp Lys Pro Asn Gly Met Lys Arg Ser Pro Ser Ala Thr Gly 1850 1855 1860 Gln Ser Ser Phe Arg Ser Thr Ala Leu Pro Glu Lys Ser Leu Ser 1865 1870 1875 Cys Ser Ser Ser Phe Pro Glu Thr Arg Ala Gly Val Arg Glu Ala 1880 1885 1890 Ser Ala Ala Ser Ser Asp Thr Ser Ser Ala Lys Ala Ala Gly Gly 1895 1900 1905 Met Leu Glu Leu Pro Ala Pro Ser Asn Arg Asp His Arg Lys Ala 1910 1915 1920 Gln Pro Ala Gly Glu Gly Arg Thr His Met Thr Lys Ser Asp Ser 1925 1930 1935 Leu Pro Ser Phe Arg Val Ser Thr Leu Pro Leu Glu Ser His His 1940 1945 1950 Pro Asp Pro Asn Thr Met Gly Gly Ala Ser His Arg Asp Arg Ala 1955 1960 1965 Leu Ser Val Thr Ala Thr Val Gly Glu Thr Lys Gly Lys Asp Pro 1970 1975 1980 Ala Pro Ala Gln Pro Pro Pro Ala Arg Lys Gln Asn Val Gly Arg 1985 1990 1995 Asp Val Thr Lys Pro Ser Pro Ala Pro Asn Thr Asp Arg Pro Ile 2000 2005 2010 Ser Leu Ser Asn Glu Lys Asp Phe Val Val Arg Gln Arg Arg Gly 2015 2020 2025 Lys Glu Ser Leu Arg Ser Ser Pro His Lys Lys Ala Leu 2030 2035 19 1770 PRT Homo sapiens misc_feature Incyte ID No 71824382CD1 19 Met Ser Gly Glu Val Arg Leu Arg Gln Leu Glu Gln Phe Ile Leu 1 5 10 15 Asp Gly Pro Ala Gln Thr Asn Gly Gln Cys Phe Ser Val Glu Thr 20 25 30 Leu Leu Asp Ile Leu Ile Cys Leu Tyr Asp Glu Cys Asn Asn Ser 35 40 45 Pro Leu Arg Arg Glu Lys Asn Ile Leu Glu Tyr Leu Glu Trp Ala 50 55 60 Lys Pro Phe Thr Ser Lys Val Lys Gln Met Arg Leu His Arg Glu 65 70 75 Asp Phe Glu Ile Leu Lys Val Ile Gly Arg Gly Ala Phe Gly Glu 80 85 90 Val Ala Val Val Lys Leu Lys Asn Ala Asp Lys Val Phe Ala Met 95 100 105 Lys Ile Leu Asn Lys Trp Glu Met Leu Lys Arg Ala Glu Thr Ala 110 115 120 Cys Phe Arg Glu Glu Arg Asp Val Leu Val Asn Gly Asp Asn Lys 125 130 135 Trp Ile Thr Thr Leu His Tyr Ala Phe Gln Asp Asp Asn Asn Leu 140 145 150 Tyr Leu Val Met Asp Tyr Tyr Val Gly Gly Asp Leu Leu Thr Leu 155 160 165 Leu Ser Lys Phe Glu Asp Arg Leu Pro Glu Asp Met Ala Arg Phe 170 175 180 Tyr Leu Ala Glu Met Val Ile Ala Ile Asp Ser Val His Gln Leu 185 190 195 His Tyr Val His Arg Asp Ile Lys Pro Asp Asn Ile Leu Met Asp 200 205 210 Met Asn Gly His Ile Arg Leu Ala Asp Phe Gly Ser Cys Leu Lys 215 220 225 Leu Met Glu Asp Gly Thr Val Gln Ser Ser Val Ala Val Gly Thr 230 235 240 Pro Asp Tyr Ile Ser Pro Glu Ile Leu Gln Ala Met Glu Asp Gly 245 250 255 Lys Gly Arg Tyr Gly Pro Glu Cys Asp Trp Trp Ser Leu Gly Val 260 265 270 Cys Met Tyr Glu Met Leu Tyr Gly Glu Thr Pro Phe Tyr Ala Glu 275 280 285 Ser Leu Val Glu Thr Tyr Gly Lys Ile Met Asn His Lys Glu Arg 290 295 300 Phe Gln Phe Pro Ala Gln Val Thr Asp Val Ser Glu Asn Ala Lys 305 310 315 Asp Leu Ile Arg Arg Leu Ile Cys Ser Arg Glu His Arg Leu Gly 320 325 330 Gln Asn Gly Ile Glu Asp Phe Lys Lys His Pro Phe Phe Ser Gly 335 340 345 Ile Asp Trp Asp Asn Ile Arg Asn Cys Glu Ala Pro Tyr Ile Pro 350 355 360 Glu Val Ser Ser Pro Thr Asp Thr Ser Asn Phe Asp Val Asp Asp 365 370 375 Asp Cys Leu Lys Asn Ser Glu Thr Met Pro Pro Pro Thr His Thr 380 385 390 Ala Phe Ser Gly His His Leu Pro Phe Val Gly Phe Thr Tyr Thr 395 400 405 Ser Ser Cys Val Leu Ser Asp Arg Ser Cys Leu Arg Val Thr Ala 410 415 420 Gly Pro Thr Ser Leu Asp Leu Asp Val Asn Val Gln Arg Thr Leu 425 430 435 Asp Asn Asn Leu Ala Thr Glu Ala Tyr Glu Arg Arg Ile Lys Arg 440 445 450 Leu Glu Gln Glu Lys Leu Glu Leu Ser Arg Lys Leu Gln Glu Ser 455 460 465 Thr Gln Thr Val Gln Ala Leu Gln Tyr Ser Thr Val Asp Gly Pro 470 475 480 Leu Thr Ala Ser Lys Asp Leu Glu Ile Lys Asn Leu Lys Glu Glu 485 490 495 Ile Glu Lys Leu Arg Lys Gln Val Thr Glu Ser Ser His Leu Glu 500 505 510 Gln Gln Leu Glu Glu Ala Asn Ala Val Arg Gln Glu Leu Asp Asp 515 520 525 Ala Phe Arg Gln Ile Lys Ala Tyr Glu Lys Gln Ile Lys Thr Leu 530 535 540 Gln Gln Glu Arg Glu Asp Leu Asn Lys Glu Leu Val Gln Ala Ser 545 550 555 Glu Arg Leu Lys Asn Gln Ser Lys Glu Leu Lys Asp Ala His Cys 560 565 570 Gln Arg Lys Leu Ala Met Gln Glu Phe Met Glu Ile Asn Glu Arg 575 580 585 Leu Thr Glu Leu His Thr Gln Lys Gln Lys Leu Ala Arg His Val 590 595 600 Arg Asp Lys Glu Glu Glu Val Asp Leu Val Met Gln Lys Val Glu 605 610 615 Ser Leu Arg Gln Glu Leu Arg Arg Thr Glu Arg Ala Lys Lys Glu 620 625 630 Leu Glu Val His Thr Glu Ala Leu Ala Ala Glu Ala Ser Lys Asp 635 640 645 Arg Lys Leu Arg Glu Gln Ser Glu His Tyr Ser Lys Gln Leu Glu 650 655 660 Asn Glu Leu Glu Gly Leu Lys Gln Lys Gln Ile Ser Tyr Ser Pro 665 670 675 Gly Val Cys Ser Ile Glu His Gln Gln Glu Ile Thr Lys Leu Lys 680 685 690 Thr Asp Leu Glu Lys Lys Ser Ile Phe Tyr Glu Glu Glu Leu Ser 695 700 705 Lys Arg Glu Gly Ile His Ala Asn Glu Ile Lys Asn Leu Lys Lys 710 715 720 Glu Leu His Asp Ser Glu Gly Gln Gln Leu Ala Leu Asn Lys Glu 725 730 735 Ile Met Ile Leu Lys Asp Lys Leu Glu Lys Thr Arg Arg Glu Ser 740 745 750 Gln Ser Glu Arg Glu Glu Phe Glu Ser Glu Phe Lys Gln Gln Tyr 755 760 765 Glu Arg Glu Lys Val Leu Leu Thr Glu Glu Asn Lys Lys Leu Thr 770 775 780 Ser Glu Leu Asp Lys Leu Thr Thr Leu Tyr Glu Asn Leu Ser Ile 785 790 795 His Asn Gln Gln Leu Glu Glu Glu Val Lys Asp Leu Ala Asp Lys 800 805 810 Lys Glu Ser Val Ala His Trp Glu Ala Gln Ile Thr Glu Ile Ile 815 820 825 Gln Trp Val Ser Asp Glu Lys Asp Ala Arg Gly Tyr Leu Gln Ala 830 835 840 Leu Ala Ser Lys Met Thr Glu Glu Leu Glu Ala Leu Arg Asn Ser 845 850 855 Ser Leu Gly Thr Arg Ala Thr Asp Met Pro Trp Lys Met Arg Arg 860 865 870 Phe Ala Lys Leu Asp Met Ser Ala Arg Leu Glu Leu Gln Ser Ala 875 880 885 Leu Asp Ala Glu Ile Arg Ala Lys Gln Ala Ile Gln Glu Glu Leu 890 895 900 Asn Lys Val Lys Ala Ser Asn Ile Ile Thr Glu Cys Lys Leu Lys 905 910 915 Asp Ser Glu Lys Lys Asn Leu Glu Leu Leu Ser Glu Ile Glu Gln 920 925 930 Leu Ile Lys Asp Thr Glu Glu Leu Arg Ser Glu Lys Gly Ile Glu 935 940 945 His Gln Asp Ser Gln His Ser Phe Leu Ala Phe Leu Asn Thr Pro 950 955 960 Thr Asp Ala Leu Asp Gln Phe Glu Asp Ser Phe Ser Ser Ser Ser 965 970 975 Ser Ser Leu Ile Asp Phe Leu Asp Asp Thr Asp Pro Val Glu Asn 980 985 990 Thr Tyr Val Trp Asn Pro Ser Val Lys Phe His Ile Gln Ser Arg 995 1000 1005 Ser Thr Ser Pro Ser Thr Ser Ser Glu Ala Glu Pro Val Lys Thr 1010 1015 1020 Val Asp Ser Thr Pro Leu Ser Val His Thr Pro Thr Leu Arg Lys 1025 1030 1035 Lys Gly Cys Pro Gly Ser Thr Gly Phe Pro Pro Lys Arg Lys Thr 1040 1045 1050 His Gln Phe Phe Val Lys Ser Phe Thr Thr Pro Thr Lys Cys His 1055 1060 1065 Gln Cys Thr Ser Leu Met Val Gly Leu Ile Arg Gln Gly Cys Ser 1070 1075 1080 Cys Glu Val Cys Gly Phe Ser Cys His Ile Thr Cys Val Asn Lys 1085 1090 1095 Ala Pro Thr Thr Cys Pro Val Pro Pro Glu Gln Thr Lys Gly Pro 1100 1105 1110 Leu Gly Ile Asp Pro Gln Lys Gly Ile Gly Thr Ala Tyr Glu Gly 1115 1120 1125 His Val Arg Ile Pro Lys Pro Ala Gly Val Lys Lys Gly Trp Gln 1130 1135 1140 Arg Ala Leu Ala Ile Val Cys Asp Phe Lys Leu Phe Leu Tyr Asp 1145 1150 1155 Ile Ala Glu Gly Lys Ala Ser Gln Pro Ser Val Val Ile Ser Gln 1160 1165 1170 Val Ile Asp Met Arg Asp Glu Glu Phe Ser Val Ser Ser Val Leu 1175 1180 1185 Ala Ser Asp Val Ile His Ala Ser Arg Lys Asp Ile Pro Cys Ile 1190 1195 1200 Phe Arg Val Thr Ala Ser Gln Leu Ser Ala Ser Asn Asn Lys Cys 1205 1210 1215 Ser Ile Leu Met Leu Ala Asp Thr Glu Asn Glu Lys Asn Lys Trp 1220 1225 1230 Val Gly Val Leu Ser Glu Leu His Lys Ile Leu Lys Lys Asn Lys 1235 1240 1245 Phe Arg Asp Arg Ser Val Tyr Val Pro Lys Glu Ala Tyr Asp Ser 1250 1255 1260 Thr Leu Pro Leu Ile Lys Thr Thr Gln Ala Ala Ala Ile Ile Asp 1265 1270 1275 His Glu Arg Ile Ala Leu Gly Asn Glu Glu Gly Leu Phe Val Val 1280 1285 1290 His Val Thr Lys Asp Glu Ile Ile Arg Val Gly Asp Asn Lys Lys 1295 1300 1305 Ile His Gln Ile Glu Leu Ile Pro Asn Asp Gln Leu Val Ala Val 1310 1315 1320 Ile Ser Gly Arg Asn Arg His Val Arg Leu Phe Pro Met Ser Ala 1325 1330 1335 Leu Asp Gly Arg Glu Thr Asp Phe Tyr Lys Leu Ser Glu Thr Lys 1340 1345 1350 Gly Cys Gln Thr Val Thr Ser Gly Lys Val Arg His Gly Ala Leu 1355 1360 1365 Thr Cys Leu Cys Val Ala Met Lys Arg Gln Val Leu Cys Tyr Glu 1370 1375 1380 Leu Phe Gln Ser Lys Thr Arg His Arg Lys Phe Lys Glu Ile Gln 1385 1390 1395 Val Pro Tyr Asn Val Gln Trp Met Ala Ile Phe Ser Glu Gln Leu 1400 1405 1410 Cys Val Gly Phe Gln Ser Gly Phe Leu Arg Tyr Pro Leu Asn Gly 1415 1420 1425 Glu Gly Asn Pro Tyr Ser Met Leu His Ser Asn Asp His Thr Leu 1430 1435 1440 Ser Phe Ile Ala His Gln Pro Met Asp Ala Ile Cys Ala Val Glu 1445 1450 1455 Ile Ser Ser Lys Glu Tyr Leu Leu Cys Phe Asn Ser Ile Gly Ile 1460 1465 1470 Tyr Thr Asp Cys Gln Gly Arg Arg Ser Arg Gln Gln Glu Leu Met 1475 1480 1485 Trp Pro Ala Asn Pro Ser Ser Cys Cys Tyr Asn Ala Pro Tyr Leu 1490 1495 1500 Ser Val Tyr Ser Glu Asn Ala Val Asp Ile Phe Asp Val Asn Ser 1505 1510 1515 Met Glu Trp Ile Gln Thr Leu Pro Leu Lys Lys Val Arg Pro Leu 1520 1525 1530 Asn Asn Glu Gly Ser Leu Asn Leu Leu Gly Leu Glu Thr Ile Arg 1535 1540 1545 Leu Ile Tyr Phe Lys Asn Lys Met Ala Glu Gly Asp Glu Leu Val 1550 1555 1560 Val Pro Glu Thr Ser Asp Asn Ser Arg Lys Gln Met Val Arg Asn 1565 1570 1575 Ile Asn Asn Lys Arg Arg Tyr Ser Phe Arg Val Pro Glu Glu Glu 1580 1585 1590 Arg Met Gln Gln Arg Arg Glu Met Leu Arg Asp Pro Glu Met Arg 1595 1600 1605 Asn Lys Leu Ile Ser Asn Pro Thr Asn Phe Asn His Ile Ala His 1610 1615 1620 Met Gly Pro Gly Asp Gly Ile Gln Ile Leu Lys Asp Leu Pro Met 1625 1630 1635 Asn Pro Arg Pro Gln Glu Ser Arg Thr Val Phe Ser Gly Ser Val 1640 1645 1650 Ser Ile Pro Ser Ile Thr Lys Ser Arg Pro Glu Pro Gly Arg Ser 1655 1660 1665 Met Ser Ala Ser Ser Gly Leu Ser Ala Arg Ser Ser Ala Gln Asn 1670 1675 1680 Gly Ser Ala Leu Lys Arg Glu Phe Ser Gly Gly Ser Tyr Ser Ala 1685 1690 1695 Lys Arg Gln Pro Met Pro Ser Pro Ser Glu Gly Ser Leu Ser Ser 1700 1705 1710 Gly Gly Met Asp Gln Gly Ser Asp Ala Pro Ala Arg Asp Phe Asp 1715 1720 1725 Gly Glu Asp Ser Asp Ser Pro Arg His Ser Thr Ala Ser Asn Ser 1730 1735 1740 Ser Asn Leu Ser Ser Pro Pro Ser Pro Val Ser Pro Arg Lys Thr 1745 1750 1755 Lys Ser Leu Ser Leu Glu Ser Thr Asp Arg Gly Ser Trp Asp Pro 1760 1765 1770 20 720 PRT Homo sapiens misc_feature Incyte ID No 3566882CD1 20 Met Ala Ala Asp Pro Thr Glu Leu Arg Leu Gly Ser Leu Pro Val 1 5 10 15 Phe Thr Arg Asp Asp Phe Glu Gly Asp Trp Arg Leu Val Ala Ser 20 25 30 Gly Gly Phe Ser Gln Val Phe Gln Ala Arg His Arg Arg Trp Arg 35 40 45 Thr Glu Tyr Ala Ile Lys Cys Ala Pro Cys Leu Pro Pro Asp Ala 50 55 60 Ala Arg Thr Phe Ala Ala Ser Val Ser Pro Leu Pro Ser Ile Tyr 65 70 75 Leu Ala Lys Ile Ser Asp Phe Gly Leu Ser Lys Trp Met Glu Gln 80 85 90 Ser Thr Arg Met Gln Tyr Ile Glu Arg Ser Ala Leu Arg Gly Met 95 100 105 Leu Ser Tyr Ile Pro Pro Glu Met Phe Leu Glu Ser Asn Lys Ala 110 115 120 Pro Gly Pro Lys Tyr Asp Val Tyr Ser Pro Pro Thr Leu Pro Pro 125 130 135 Arg Ala Gly Val Ile Leu Asp Val Gln Leu Ser His Ser Glu Arg 140 145 150 Val Leu Cys Ile His Ser Phe Ala Ile Val Ile Trp Glu Leu Leu 155 160 165 Thr Gln Lys Lys Pro Tyr Ser Glu Leu Thr Ser Gln Leu Lys Glu 170 175 180 Arg Lys Gly Phe Asn Met Met Met Ile Ile Ile Arg Val Thr Ala 185 190 195 Gly Met Arg Pro Ser Leu Gln Pro Val Ser Asp Gln Trp Pro Ser 200 205 210 Glu Ala Gln Gln Met Val Asp Leu Met Lys Arg Cys Trp Asp Gln 215 220 225 Asp Pro Lys Lys Arg Pro Cys Phe Leu Asp Ile Thr Ile Glu Thr 230 235 240 Asp Ile Leu Leu Ser Leu Leu Gln Ser Arg Val Ala Val Pro Glu 245 250 255 Ser Lys Ala Leu Ala Arg Lys Val Ser Cys Lys Leu Ser Leu Arg 260 265 270 Gln Pro Gly Glu Val Asn Glu Asp Ile Ser Gln Glu Leu Met Asp 275 280 285 Ser Asp Ser Gly Asn Tyr Leu Lys Arg Ala Leu Gln Leu Ser Asp 290 295 300 Arg Lys Asn Leu Val Pro Arg Asp Glu Glu Leu Cys Ile Tyr Glu 305 310 315 Asn Lys Val Thr Pro Leu His Phe Leu Val Ala Gln Gly Ser Val 320 325 330 Glu Gln Val Arg Leu Leu Leu Ala His Glu Val Asp Val Asp Cys 335 340 345 Gln Thr Ala Ser Gly Tyr Thr Pro Leu Leu Ile Ala Ala Gln Asp 350 355 360 Gln Gln Pro Asp Leu Cys Ala Leu Leu Leu Ala His Gly Ala Asp 365 370 375 Ala Asn Arg Val Asp Glu Asp Gly Trp Ala Pro Leu His Phe Ala 380 385 390 Ala Gln Asn Gly Asp Asp Gly Thr Ala Arg Leu Leu Leu Asp His 395 400 405 Gly Ala Cys Val Asp Ala Gln Glu Arg Glu Gly Trp Thr Pro Leu 410 415 420 His Leu Ala Ala Gln Asn Asn Phe Glu Asn Val Ala Arg Leu Leu 425 430 435 Val Ser Arg Gln Ala Asp Pro Asn Leu His Glu Ala Glu Gly Lys 440 445 450 Thr Pro Leu His Val Ala Ala Tyr Phe Gly His Val Ser Leu Val 455 460 465 Lys Leu Leu Thr Ser Gln Gly Ala Glu Leu Asp Ala Gln Gln Arg 470 475 480 Asn Leu Arg Thr Pro Leu His Leu Ala Val Glu Arg Gly Lys Val 485 490 495 Arg Ala Ile Gln His Leu Leu Lys Ser Gly Ala Val Pro Asp Ala 500 505 510 Leu Asp Gln Ser Gly Tyr Gly Pro Leu His Thr Ala Ala Ala Arg 515 520 525 Gly Lys Tyr Leu Ile Cys Lys Met Leu Leu Arg Tyr Gly Ala Ser 530 535 540 Leu Glu Leu Pro Thr His Gln Gly Trp Thr Pro Leu His Leu Ala 545 550 555 Ala Tyr Lys Gly His Leu Glu Ile Ile His Leu Leu Ala Glu Ser 560 565 570 His Ala Asn Met Gly Ala Leu Gly Ala Val Asn Trp Thr Pro Leu 575 580 585 His Leu Ala Ala Arg His Gly Glu Glu Ala Val Val Ser Ala Leu 590 595 600 Leu Gln Cys Gly Ala Asp Pro Asn Ala Ala Glu Gln Ser Gly Trp 605 610 615 Thr Pro Leu His Leu Ala Val Gln Arg Ser Thr Phe Leu Ser Val 620 625 630 Ile Asn Leu Leu Glu His His Ala Asn Val His Ala Arg Asn Lys 635 640 645 Val Gly Trp Thr Pro Ala His Leu Ala Ala Leu Lys Gly Asn Thr 650 655 660 Ala Ile Leu Lys Val Leu Val Glu Ala Gly Ala Gln Leu Asp Val 665 670 675 Gln Asp Gly Val Ser Cys Thr Pro Leu Gln Leu Ala Leu Arg Ser 680 685 690 Arg Lys Gln Gly Ile Met Ser Phe Leu Glu Gly Lys Glu Pro Ser 695 700 705 Val Ala Thr Leu Gly Gly Ser Lys Pro Gly Ala Glu Met Glu Ile 710 715 720 21 5200 DNA Homo sapiens misc_feature Incyte ID No 4615110CB1 21 cgtggctgag ccagcagctg cagcagctac gggagtggcc gggtggccgg cgggtgccag 60 ccgccatgga ggccgtgccc cgcatgccca tgatctggct ggacctgaag gaggccggtg 120 actttcactt ccagccagct gtgaagaagt ttgtcctgaa gaattatgga gagaacccag 180 aagcctacaa tgaagaactg aagaagctgg agttgctcag acagaatgct gtccgtgtcc 240 cacgagactt tgagggctgt agtgtcctcc gcaagtacct cggccagctt cattacctgc 300 agagtcgggt ccccatgggc tcgggccagg aggccgctgt ccctgtcacc tggacagaga 360 tcttctcagg caagtctgtg gcccatgagg acatcaagta cgagcaggcc tgtattctct 420 acaaccttgg agcgctgcac tccatgctgg gggccatgga caagcgggtg tctgaggagg 480 gcatgaaggt ctcctgtacc catttccagt gcgcagccgg cgccttcgcc tacctacggg 540 agcacttccc tcaagcctac agcgtcgaca tgagccgcca gatccttacg ctcaacgtca 600 acctcatgct gggccaggct caggagtgcc tcctggagaa gtcgatgttg gacaacagga 660 agagctttct ggtggcccgc atcagtgcac aggtggtaga ttactacaag gaggcatgcc 720 gggccttgga gaaccccgac actgcctcac tgctgggccg gatccagaag gactggaaga 780 aacttgtgca gatgaagatc tactacttcg cagccgtggc tcatctgcac atgggaaagc 840 aggccgagga gcagcagaag ttcggggagc gggttgcata cttccagagc gccctggaca 900 agctcaatga agccatcaag ttggccaagg gccagcctga cactgtgcaa gacgcgcttc 960 gcttcactat ggatgtcatt gggggaaagt acaattctgc caagaaggac aacgacttca 1020 tttaccatga ggctgtccca gcattggaca cccttcagcc tgtaaaagga gcccccttgg 1080 tgaagccctt gccagtgaac cccacagacc cagctgttac aggccctgac atctttgcca 1140 aactggtacc catggctgcc cacgaggcct cgtcactgta cagtgaggag aaggccaagc 1200 tgctccggga gatgatggcc aagattgagg acaagaatga ggtcctggac cagttcatgg 1260 attcaatgca gttggatccc gagacggtgg acaaccttga tgcctacagc cacatcccac 1320 cccagctcat ggagaagtgc gcggctctca gcgtccggcc cgacactgtc aggaaccttg 1380 tacagtccat gcaagtgctg tcaggtgtgt tcacggatgt ggaggcttcc ctgaaggaca 1440 tcagagatct gttggaggag gatgagctgc tagagcagaa gtttcaggag gcggtgggcc 1500 aggcaggggc catctccatc acctccaagg ctgagctggc agaggtgagg cgagaatggg 1560 ccaagtacat ggaagtccat gagaaggcct ccttcaccaa cagtgagctg caccgtgcca 1620 tgaacctgca cgtcggcaac ctgcgcctgc tcagcgggcc gcttgaccag gtccgggctg 1680 ccctgcccac accggccctc tccccagagg acaaggccgt gctgcaaaac ctaaagcgca 1740 tcctggctaa ggtgcaggag atgcgggacc agcgcgtgtc cctggagcag cagctgcgtg 1800 agcttatcca gaaagatgac atcactgcct cgctggtcac cacagaccac tcagagatga 1860 agaagttgtt cgaggagcag ctgaaaaagt atgaccagct gaaggtgtac ctggagcaga 1920 acctggccgc ccaggaccgt gtcctctgtg cactgacaga ggccaacgtg cagtacgcag 1980 ccgtgcggcg ggtactcagc gacttggacc aaaagtggaa ctccacgctg cagaccctgg 2040 tggcctcgta tgaagcctat gaggacctga tgaagaagtc gcaggagggc agggacttct 2100 acgcagatct ggagagcaag gtggctgctc tgctggagcg cacgcagtcc acctgccagg 2160 cccgcgaggc tgcccgccag cagctcctgg acagggagct gaagaagaag ccgccgccac 2220 ggcccacagc cccaaagccg ctgctgcccc gcagggagga gagtgaggca gtggaagcag 2280 gagacccccc tgaggagctg cgcagcctcc cccctgacat ggtggctggc ccacgactgc 2340 ctgacacctt cctgggaagt gccaccccgc tccactttcc tcccagcccc ttccccagct 2400 ccacaggccc aggaccccac tatctctcag gccccttgcc ccctggtacc tactcgggcc 2460 ccacccagct gatacagccc agggccccag ggccccatgc aatgcccgta gcacctgggc 2520 ctgccctcta cccagcccct gcctacacac cggagctggg ccttgtgccc cgatcctccc 2580 cacagcatgg cgtggtgagc agtccctatg tgggggtagg gccggcccca ccagttgcag 2640 gtctcccctc ggccccacct cctcaattct caggccccga gttggccatg gcggttcggc 2700 cagccaccac cacagtagat agcatccagg cgcccatccc cagccacaca gccccacggc 2760 caaaccccac ccctgctcct cccccgccct gcttccctgt gcccccaccg cagccactgc 2820 ccacgcctta cacctaccct gcaggggcta agcaacccat cccagcacag caccacttct 2880 cttctgggat ccccacaggt tttccagccc caaggattgg gccccagccc cagccccatc 2940 ctcagcccca tccttcacaa gcgtttgggc ctcagccccc acagcagccc cttccactcc 3000 agcatccaca tctcttccca ccccaggccc caggactcct acccccacaa tccccctacc 3060 cctatgcccc tcagcctggg gtcctggggc agccgccacc ccccctacac acccagctct 3120 acccaggtcc cgctcaagac cctctgccag cccactcagg ggctctgcct ttccccagcc 3180 ctgggccccc tcagcctccc catcccccac tggcatatgg tcctgcccct tctaccagac 3240 ccatgggccc ccaggcagcc cctcttacca ttcgagggcc ctcgtctgct ggccagtcca 3300 cccctagtcc ccacctggtg ccttcacctg ccccatctcc agggcctggt ccggtacccc 3360 ctcgcccccc agcagcagaa ccaccccctt gcctgcgccg aggcgccgca gctgcagacc 3420 tgctctcctc cagcccggag agccagcatg gcggcactca gtctcctggg ggtgggcagc 3480 ccctgctgca gcccaccaag gtggatgcag ctgagggtcg tcggccgcag gccctgcggc 3540 tgattgagcg ggacccctat gagcatcctg agaggctgcg gcagttgcag caggagctgg 3600 aggcctttcg gggtcagctg ggggatgtgg gagctctgga cactgtctgg cgagagctgc 3660 aagatgcgca ggaacatgat gcccgaggcc gttccatcgc cattgcccgc tgctactcac 3720 tgaagaaccg gcaccaggat gtcatgccct atgacagtaa ccgtgtggtg ctgcgctcag 3780 gcaaggatga ctacatcaat gccagctgcg tggaggggct ctccccatac tgccccccgc 3840 tagtggcaac ccaggcccca ctgcctggca cagctgctga cttctggctc atggtccatg 3900 agcagaaagt gtcagtcatt gtcatgctgg tttctgaggc tgagatggag aagcaaaaag 3960 tggcacgcta cttccccacc gagaggggcc agcccatggt gcacggtgcc ctgagcctgg 4020 cattgagcag cgtccgcagc accgaaaccc atgtggagcg cgtgctgagc ctgcagttcc 4080 gagaccagag cctcaagcgc tctcttgtgc acctgcactt ccccacttgg cctgagttag 4140 gcctgcccga cagccccagc aacttgctgc gcttcatcca ggaggtgcac gcacattacc 4200 tgcatcagcg gccgctgcac acgcccatca ttgtgcactg cagctctggt gtgggccgca 4260 cgggagcctt tgcactgctc tatgcagctg tgcaggaggt ggaggctggg aacggaatcc 4320 ctgagctgcc tcagctggtg cggcgcatgc ggcagcagag aaagcacatg ctgcaggaga 4380 agctgcacct caggttctgc tatgaggcag tggtgagaca cgtggagcag gtcctgcagc 4440 gccatggtgt gcctcctcca tgcaaaccct tggccagtgc aagcatcagc cagaagaacc 4500 accttcctca ggactcccag gacctggtcc tcggtgggga tgtgcccatc agctccatcc 4560 aggccaccat tgccaagctc agcattcggc ctcctggggg gttggagtcc ccggttgcca 4620 gcttgccagg ccctgcagag cccccaggcc tcccgccagc cagcctccca gagtctaccc 4680 caatcccatc ttcctcccca cccccccttt cctccccact acctgaggct ccccagccta 4740 aggaggagcc gccagtgcct gaagccccca gctcggggcc cccctcctcc tccctggaat 4800 tgctggcctc cttgacccca gaggccttct ccctggacag ctccctgcgg ggcaaacagc 4860 ggatgagcaa gcataacttt ctgcaggccc ataacgggca agggctgcgg gccacccggc 4920 cctctgacga ccccctcagc cttctggatc cactctggac actcaacaag acctgaacag 4980 gttttgccta cctggtcctt acactacatc atcatcatct catgcccacc tgcccacacc 5040 cagcagagct tctcagtggg cacagtctct tactcccatt tctgctgcct ttggccctgc 5100 ctggcccagc ctgcacccct gtggggtgga aatgtactgc aggctctggg tcaggttctg 5160 ctcctttatg ggacccgaca tttttcagct ctttgctatt 5200 22 4330 DNA Homo sapiens misc_feature Incyte ID No 4622229CB1 22 ctgaggcggg cgggcggtat agagcgggcg gcaggaggca agcagcgaaa ccttcccggc 60 cgccgctccc gtcccgacgg cggcttcccc aaggcggcag gactcggcgc gccatggaca 120 ggccggcggc ggcggcggcg gcgggctgcg agggcggcgg gggcccgaac ccggggccgg 180 cgggcggcag gaggcctcct cgggccgcgg ggggcgccac cgccggctcc cggcagccca 240 gcgtggagac cctggacagt cccacaggat cacatgttga atggtgtaaa cagcttatag 300 ctgctacaat ttctagtcag atttcaggtt cagtgacatc agaaaatgtg tccagagatt 360 acaaggtttt caggaggcct gatctaaggg ctctaaggga tggaaataag ctggcacaga 420 tggaagaggc tccacttttc ccaggagaat caattaaagc cattgtgaaa gatgtcatgt 480 atatctgccc atttatggga gcagtgagtg gaaccctgac agtgacggac tttaagctgt 540 acttcaaaaa tgtcgagagg gacccgcatt ttatccttga tgttcccctt ggagtgatca 600 gcagagtgga gaagattgga gcacagagcc atggagacaa ttcctgtggt atagagatag 660 tgtgcaagga tatgaggaac ttgcggcttg cttataaaca ggaagaacag agtaaactag 720 ggatatttga aaacctcaac aaacatgcat ttcctctttc taacggacag gcactatttg 780 cattcagcta taaagaaaaa tttccaatta atggctggaa agtttatgat ccagtatctg 840 aatataagag acagggcttg ccaaatgaga gttggaaaat atccaaaata aacagtaatt 900 atgagttctg tgacacctac cctgccatca ttgttgtgcc aactagtgta aaagatgatg 960 acctttcaaa agtggcagct tttcgagcaa aaggcagagt ccctgtgttg tcatggattc 1020 atccggaaag tcaagcaacg attacccgtt gcagccagcc acttgtgggt cccaatgata 1080 agcgctgcaa agaggatgaa aaatacttgc aaacaataat ggatgctaac gcacagtcac 1140 acaagcttat catctttgat gctcgacaaa acagtgtcgc tgataccaac aagacaaagg 1200 gtggaggata tgaaagtgaa agtgcttacc caaatgcaga acttgtgttc ttggagatcc 1260 acaacattca tgtcatgcga gagtcactac gcaaattaaa agagattgtg tacccttcga 1320 tcgatgaggc gcggtggctc tccaatgtgg atgggacgca ttggctggaa tatataagga 1380 tgctgcttgc tggggcagta agaattgctg ataaaataga atctgggaaa acatctgtgg 1440 tggtgcattg cagcgacggt tgggaccgaa cagcccagct cacatctctg gctatgctaa 1500 tgttggacag ttactacagg accattaaag gatttgaaac tctcgtagaa aaggagtgga 1560 taagctttgg acacaggttt gcactgcgag tgggccatgg taatgacaac catgcggatg 1620 ctgaccgatc tcccatattt ctgcagtttg ttgattgtgt ttggcaaatg acaaggcagt 1680 ttccttcagc attcgagttt aatgagctat tcttgattac aattttggat cacctttata 1740 gctgtctttt tgggaccttt ttgtgcaact gtgaacagca gcgattcaaa gaggatgtat 1800 atacaaagac gatatcttta tggtcgtata tcaatagcca gctagacgag ttttctaatc 1860 ccttctttgt gaattatgaa aaccacgtgt tatatcctgt tgctagtctg agtcatttgg 1920 aattgtgggt aaattattat gtacgatgga atccacggat gagacctcag atgcccattc 1980 accagaatct caaggagctg ctggccgtca gggcggagct gcagaagcgt gtggagggtc 2040 tacagcggga ggtggccacg cgcgccgtct catcctcatc tgagcggggc tcctcgccct 2100 cccactccgc cacctccgtc cacacctcgg tctgatgggc gaggtcagcc tgctgctcca 2160 ctgtctcccg gtggctcagg aaagggacct ggcgatcact gttatggctg tagcttgtga 2220 tcttgtcttt taggattagg cccagggacc atttgtgtgg ctaggtgaca gctcccactg 2280 ttggcaaccg ttaccctcct gtcagcggtt tcacagggga gccgtctgtc acgcccaccc 2340 tgtgaagcaa cttctggcat tcaggcagct tgggagaaac taagtgaacg gaatgcagta 2400 ctgaggttca agaaagctgt acgccatttc tttccaactt aaatccttca gtaacaacaa 2460 acaccactca cttcaagatg cattgccagc cccgtggctt ccctcagctc ttggccacaa 2520 cttgaaaact gtcttgaatg aagtacttgg ggagaagaca ggccactgcc ctctgttcca 2580 cagttttctt catgcacggg gtcctcctgt taacaattac tgttgtgtac atataaggta 2640 tttttagaga agagaaacag gcctttattt tcctatgtcc ttttttacgt ttagaatagt 2700 cacccgaggg gggatcagct caactgtact gtgggagaaa ttcttttcca acaaacctca 2760 tgctcgtttt tctgtggtgc aatttcaagg gcaacgtgtt ctgtcctcac ctcactctgg 2820 tactcgcctc ttggggcggc tcagcccatt catggggatg gcaccaagcg gccatgctca 2880 gtcttccagc cccgctgagg gtaaaccgag gcctctggca gctgtgcaca ggtgctggcc 2940 tctggctcct tcaaggagca ctgcctgtca ctcgctcctg ggctgtctag ccatgtctcc 3000 cacccccact ttaccgcagc cagctgctgg gatcaaagca agtctgttct tatgttattt 3060 gcctgtatga aatcatttct cattttatca caattccttc aactcagctt actcgcgtgg 3120 ctgcctgttc atatttgaaa gcagccaccg tgctgtggct ttggtttgga aaagcatagc 3180 acgcacttcc cttggttttc ccttcccaga gccgaccgca gctggtcagc cctctcttcc 3240 cgctcctgaa cctttactta ctgactttga gctctgtgac tccgtcggtt ctcgcaggaa 3300 ttaactaact taccaattgg ttcaatccac ttgagcgcca tagctctgag ctcctctgtg 3360 tgacatgcca cagatgacta ttgcacacct gggtcctgcc ccagcaggcc atgcccctcc 3420 catgtgccgt gcctgttgct gcagctgccc ccccaccccg ccactggctg caggaattca 3480 gcctttagag gcagaggcag ctgcagcggc ccctgaggtc aaaccccagt gtgactgcat 3540 agcagtgtta gctggttggt ttcaaactac tggattccag gcaaaggcct acagattgac 3600 cttattattt ttgaaaatat gttaagggtt ttttcataga gagagaaaga atggattttt 3660 ttttaactgg gaacctcctg attcttacgg aaaattatcc ttctataaga agataccaga 3720 gagatttatt caaggtaatt tgataaccta aaatcaattc tccatttttt atcatatgtg 3780 ggatttgttg ctaagtcgtg ttcaacaata gcttttatgt tcctaacata tctgaaagct 3840 tatttatgaa tggatatact ggattattga tatactgatt ttttttttaa tggggacatt 3900 tgccattttc ttcccagaaa tatgtaatcc cctggctgac taggactgtt aaacatagtg 3960 tggactggac gatgccttcg acaaaccaga gaaaccaagt tggggggagc tggtgcctgg 4020 agtgggccct gtgcacctca cctggcggag gctggggggg ctctgtcagc aggaccctag 4080 aggagactct cattcgattt taaagaagca caacgggtca ttttcctttg tatgttccta 4140 gcgcagaact gtttctaaaa caacttgaag tatagttttg ttatctaagc aatttttgtt 4200 ttaagtaagt aagtgtacta gaatgcgaag ccgttatggt tcaggttttt aaaaactggt 4260 acagtattgt atttgtctca tctgttgcac tgtatttcaa tcatctgtaa ttaaaatgat 4320 catatgttta 4330 23 2851 DNA Homo sapiens misc_feature Incyte ID No 72358203CB1 23 atcttgaatg cagggacagc catttggaag actgtcctcg agggtggcag cagcctctca 60 ggacggggaa agccaaggtg cccactaagc ccgtctgggg tggagggtgg caggccgggg 120 tggagaggat tggaggccgc ctgaaggaac ctgtgctcgg tggcatttac tcaatgtggg 180 ggtctgacac ctcccagctc attttgtccc catcttcccc ttgcgtcagg tccccaccca 240 gcaggaggag gtccgaggat ctgcgcgacg ctggccccgc ggagtgtggg ggacttttcc 300 tctcaaccac cagtgccccg caagcgtggg tgaacagtcc tccctggcta ctgtgggacg 360 ctgggcaggc gacttcgcct ctctaggcct cggttttcct gcttgtcaaa tggggctgat 420 gccggcgtgg gcttcttcag gcggtcgcga gcgttgaccc ctggagtcag cgaaccagcc 480 gcgcacgcac tcccgggcgg aggtcggggc tggggggcga cgcctcccgt ctgcgcgccc 540 ccggccccgc ctcccgccgg cgcacccctc cctcggctcc gcccgcggcc cgcttcttcc 600 tcccgcgggc ggcccagccc tagcgccccg cgctccgcgg gcagccccct gccgccgcgc 660 catgtccgcc ggctggttcc ggcgccgctt cctgcctggg gagccgctcc ccgcgccgcg 720 gccgcctggg ccgcatgcca gccccgtgcc ctaccgacgg ccccgcttcc ttcgcggctc 780 cagctccagc cccggggcgg ccgacgcctc gcgccgccca gactcccggc ccgtgcgcag 840 ccccgcacga ggacgcacgc taccctggaa tgcaggctac gccgagatta tcaatgcaga 900 gaaatctgaa ttcaatgagg atcaagccgc ctgtgggaag ctgtgcatcc ggagatgtga 960 gtttggggct gaagaagagt ggctgaccct gtgcccagag gagttcctga caggccatta 1020 ctgggcactg ttcgatgggc acggcggtcc tgcagcagcc atcttggctg ccaacaccct 1080 gcactcctgc ttgcgccggc agctggaggc cgtggtggaa ggcttggtgg ccactcagcc 1140 ccccatgcac ctcaatggcc gctgcatctg ccccagtgac cctcagtttg tggaggaaaa 1200 gggcatcagg gcagaagact tggtgatcgg ggcattggag agtgcctttc aggaatgtga 1260 tgaggtgatc gggcgggagc tggaggcctc aggccagatg ggcggctgca cagccctggt 1320 ggctgtgtcc ctgcagggaa agctgtacat ggccaatgct ggggatagca gggccatctt 1380 ggtgcggaga gatgagatac ggccactgag cttcgagttc accccagaga ctgagcggca 1440 gcggatccag cagctggcct ttgtctatcc tgagcttctg gctggtgagt tcacccgact 1500 ggagttccct cggcggctga agggggatga cttgggacag aaggttttgt tcagggatca 1560 ccacatgagt ggctggagct acaaacgtgt ggagaaatcg gatctcaagt acccactgat 1620 ccatggacag ggtaggcagg ctcggttact aggaacactg gctgtctccc ggggcctggg 1680 agaccatcag ctcagagtcc tggacacaaa catccagctc aagcccttct tgctctctgt 1740 gccacaggtg actgtgctgg atgtggacca gctggagcta caggaggatg atgtggttgt 1800 catggcaact gatggactct gggatgtact gtccaacgag caggtggcat ggctggtgcg 1860 gagcttcctc cctgggaacc aagaggaccc acacaggttc tcaaagctgg cccagatgct 1920 gatacacagc acacagggaa aggaagacag tctcacagag gaagggcagg tgtcctacga 1980 tgacgtctct gtgttcgtga ttcccttgca cagtcagggc caagagagca gtgaccactg 2040 aggattcaga cactgtatcc cagaactgct ctagtgcccg ggtgtggtct gggcatccct 2100 ccagtgtgac caagagcaaa tcctgcctgc cctatcccta gccaccgccc agtgctctca 2160 ctatccacct caacacacat ccatctcaag aggaacattt ataccaggca gtcagagctg 2220 gaagtgtatg gagagcccag cccaccaggt cctgcctttt gcggtgataa ccttctctgg 2280 cagagtgact ttacaactta actaggaaac ccatgtgagg ctcctcagac aggatcttga 2340 acagcccaaa gtatcattct cagatagggg cacccaagct aagggtatta gccaaagatg 2400 ccaggatggg tagctagccc atgtttagat ccaggtctcc aattcatggt tatcagggca 2460 tgtgttcaac aacccccaaa gtccacgcag gtggcttgta gaaacctttg ggcagcctca 2520 tgtctgctaa aacagccatc ttcaagacag cccctgaaaa gagaccagtt caggtcctgc 2580 cctgctgttc tttgctggag atgaggaaca ggtgctgggg ctaaagtttg gggtagagca 2640 caagggacaa gaggaactct tggagttggc tgggtgagag ggctctccat ttgctacctg 2700 tagtagcctg cctcttaact ggttgcttct ccctagttcc agccctgccc tggtctgatg 2760 ccccaacact gcccttgctt tgttttccct gtcacctccc tattattaaa tgttttctac 2820 agaaaaaaaa aaaaaaaaaa aaaaaaaaaa a 2851 24 2361 DNA Homo sapiens misc_feature Incyte ID No 4885040CB1 24 ggctcctacc agccattgta ggccaataat ccgttatgga gcatgccttt accccgttgg 60 agcccctgct ttccactggg aatttgaagt actgccttgt aattcttaat cagcctttgg 120 acaactattt tcgtcatctt tggaacaaag ctcttttaag agcctgtgcc gatggaggtg 180 ccaaccgctt atatgatatc accgaaggag agagagaaag ctttttgcct gaattcatca 240 atggagactt tgattctatt aggcctgaag tcagagaata ctatgctact aagggatgtg 300 agctcatttc aactcctgat caagaccaca ctgactttac taagtgcctt aaaatgctcc 360 aaaagaagat agaagaaaaa gacttaaagg ttgatgtgat cgtgacactg ggaggccttg 420 ctgggcgttt tgaccagatt atggcatctg tgaatacctt gttccaagcg actcacatca 480 ctccttttcc aattataata atccaagagg aatcgctgat ctacctgctc caaccaggaa 540 agcacaggtt gcatgtagac actggaatgg agggtgattg gtgtggcctt attcctgttg 600 gacagccttg tatgcaggtt acaaccacag gcctcaagtg gaacctcaca aatgatgtgc 660 ttgcttttgg aacattggtc agtacttcca atacctacga cgggtctggt gttgtgactg 720 tggaaactga ccacccactc ctctggacca tggccatcaa aagctaacct gttgactggc 780 atccataagt gtgcctctgc cttatctcat ttctcaacag ttcattgctc aacaagaacg 840 attcacctgg gtttgcaaga atctaaacct ctctagggga agcccactgg gtttaaagat 900 gttagtgttt agataataca ggtaacatta taaatgacag atctcaattt tatagtagtg 960 ggaaagatac atgctaagaa agcaaataag ctctattata ttcggttgga acctaatggg 1020 aatcattcca ctatacaatt cagtactgat tattcttctt acattattaa tcattccatt 1080 tatcctagaa aattgttttt aatttgaatc agagaaaact gttgaggttc ctcttggagt 1140 ctagaacatc cttaaatgtc taacaacaag ggctacctct gagtaccttt tagtattagt 1200 tttctgtata tgatatatat tatcttatac tgaaaaaaaa ttcctttcag attggggtgt 1260 tagaagtgca ccaggtcact ctgaccttat tactgtcttt ggtattgtct taaataaatc 1320 aagaatcatt gacctaattg ttaaatttaa aaataggtag ttagcaatag gtggaaagag 1380 aaatgatgtg aaagataaat gatgattcgt ggagccctac tcacacatta acccccaaat 1440 tcaaaagtaa gaatgcaaaa gtctagaggg ggtaacagtc tgcatcatca tcacaaccta 1500 aatggagaaa gctgtgcaga ggaaacttaa gcataaaaat tgaattcgtt tctgacatac 1560 cttagactga aaaactgttg gttcatccag aagtgtattc atattaccag aaaatgagtt 1620 tgtctatggg gatacatgaa cttcatatac taaggagcct aactccaaag cctgcgttct 1680 catcccagtc tgatattcac ctaagtttcc ggaccctttt ccttagctgt aaaatggaag 1740 cggttggact gatggtgtct gaggttcttt cccacactga aattctaaat attgacactt 1800 agcagtcata gggctgataa tacacacagt tactgactta gcctaaacaa cctggtgcat 1860 cgaaatgtat tcacctttct tttgtaaaga gaccatcttc tatcttcttt ccacctttct 1920 ctgttttatg aaaccaactg ttgacataca aaccatgatt gaaggagaac ctgtccaaca 1980 tgttttatgt acacaaatcc ctatgttgct ataagaaaag tgaaagtaac tgttttcttc 2040 ttggtgctat gacagtgtga gactcaggtt gtctgtagag aatgaaagga gcagtggccc 2100 gcgtgattgt ggcatttaag gagcagtggc ccatgtgact gtggcatttt cggcactttt 2160 cattactttc tgcttgaccg gaagttgagg cttagctatg tttccatctt cagtttctga 2220 agactagtta tatattcctt actagaaata tattcataat atataaaaga aatatatctg 2280 tgattttaaa attttgctac caaagaatgc atgttctgtg tgccctgaaa atgttaccag 2340 tgttaataaa tggatactta t 2361 25 2285 DNA Homo sapiens misc_feature Incyte ID No 7484507CB1 25 gcggtccctc ccggcccggc ggaacgcgtc ccttttaagg gggcggggac ctgggggtct 60 ggggccagcg cgcgggaggg acgcctgagt gcctcgaggg cgccgttcgg gcggggagga 120 tcccgcgggt cccactgacc cacgcggggt ggggccaggg gtggacgctc gcccgtacgc 180 ggtcgctact gatcatgctt gggccagggt ccaatcgcag gcgccccacg cagggggagc 240 gaggcccagg gtcccccgga gagcccatgg agaagtacca ggttttgtac cagctgaatc 300 ctggggcctt gggggtgaac ctggtggtgg aggaaatgga aaccaaagtc aagcatgtga 360 taaagcaggt ggaatgcatg gatgaccatt acgccagtca ggccctggag gagctgatgc 420 cactgctgaa gctgcggcac gcccacatct ctgtgtacca ggagctgttc atcacgtgga 480 atggggagat ctcttctctg tacctctgcc tggtgatgga gttcaatgag ctcagcttcc 540 aggaggtcat tgaggataag aggaaggcaa agaaaatcat tgactctgag tggatgcaga 600 atgtgctggg ccaggtgctg gacgcgctgg aatacctgca ccatttggac atcatccaca 660 ggaatctcaa accctccaac atcatcctca tcagcagtga ccactgcaaa ctgcaggacc 720 tgagttccaa tgtgctaatg acagacaaag ccaaatggaa tattcgtgcg gaggaagacc 780 cctttcgtaa gtcctggatg gcccctgaag ccctcaactt ctccttcagc cagaaatcag 840 acatctggtc cctgggctgc atcattctgg acatgaccag ctgctccttc atggatggca 900 cagaagccat gcatctgcgg aagtccctcc gccagagccc aggcagcctg aaggccgtcc 960 tgaagacaat ggaggagaag cagatcccgg atgtggaaac cttcaggaat cttctgccct 1020 tgatgctcca gatcgacccc tcggatcgaa taacgataaa ggacgtggtg cacatcacct 1080 tcttgagagg ctccttcaag tcctcgtgcg tctctctgac cctgcaccgg cagatggtgc 1140 ctgcgtccat caccgacatg ctgttagaag gcaacgtggc cagcatttta ggtgatgctg 1200 gggacacaaa gggggagcgt gccctgaagc tcctgtccat ggccttggca tcctattgtt 1260 tagttccaga gggttcatta tttatgcccc tggccttgct ccacatgcac gaccagtggc 1320 tcagctgtga ccaggacaga gtccctggga agagagactt tgcctccctg gggaaactag 1380 ggaagctgtt gggccccatc ccaaagggtc tgccgtggcc cccggagctg gtggaggtgg 1440 tggtcacgac catggagcta catgacaggg tcctcgatgt ccagctgtgt gcctgctccc 1500 tgctgctgca cctcctgggc caaggtatca ttgtgaacaa ggcccccttg gagaaggtcc 1560 cggacctcat cagccaggtg ttggccacct accctgcgga tggggaaatg gcagaagcca 1620 gctgcggagt cttctggctg ctgtccctgc tgggctgcat caaggagcag cagtttgaac 1680 aagtggtggc gctgctcctg caaagcatcc ggctgtgcca ggacagagcc ctgctggtga 1740 acaatgccta ccggggactg gccagcctgg tgaaggtgtc agagctggcg gccttcaagg 1800 tggtggtgca ggaggagggc ggcagtggcc tcagcctcat caaggagacc taccagctcc 1860 acagggacga cccggaggtg gtggagaacg tgggcatgct gctggtccac ctggcttcct 1920 atgaggagat cctgccggag ctggtgtcca gtagtatgaa ggccctgctc caggagatca 1980 aggagcgctt cacctccagc ctggaactgg tttcttgcgc ggaaaaagtg ctcttgaggc 2040 tggaggcagc cacctctccc agcccactgg gtggggaagc agctcagccc tgatgcgggg 2100 gagaagacag ataccccaca ggcccctccc tccacgtgtg ccctctccct gtccttcctt 2160 tccatgggcc actgtttccc ttggggtggg gggaagggtc atccagcacc agaatgcgca 2220 cctcacactc ctcttaggtg actaataaag aggcccaagg ccagtttctg ccttaaaaaa 2280 aaaaa 2285 26 4858 DNA Homo sapiens misc_feature Incyte ID No 7198931CB1 26 atggcggcgg cggcggggaa tcgcgcctcg tcgtcgggat tcccgggcgc cagggctacg 60 agccctgagg caggcggcgg cggaggagcc ctcaaggcga gcagcgcgcg cgcggctgcc 120 gcgggactgc tgcgggaggc gggcagcggg ggccgcgagc gggcggactg gcggcggcgg 180 cagctgcgca aagtgcggag tgtggagctg gaccagctgc ctgagcagcc gctcttcctt 240 gccgcctcac cgccggcctc ctcgacttcc ccgtcgccgg agcccgcgga cgcagcgggg 300 agtgggaccg gcttccagcc tgtggcggtg ccgccgcccc acggagccgc cagccggcgc 360 ggcgcccacc ttaccgagtc ggtggcggcg ccggacagcg gcgcctcgag tcccgcagcg 420 gccgagcccg gggagaagcg ggcgcccgcc gccgagccgt ctcctgcagc ggcccccgcc 480 ggtcgtgaga tggagaataa agaaactctc aaagggttgc acaagatgga tgatcgtcca 540 gaggaacgaa tgatcaggga gaaactgaag gcaacctgta tgccagcctg gaagcacgaa 600 tggttggaaa ggagaaatag gcgagggcct gtggtggtaa aaccaatccc agttaaagga 660 gatggatctg aaatgaatca cttagcagct gagtctccag gagaggtcca ggcaagtgcg 720 gcttcaccag cttccaaagg ccgacgcagt ccttctcctg gcaactcccc atcaggtcgc 780 acagtgaaat cagaatctcc aggagtaagg agaaaaagag tttccccagt gccttttcag 840 agtggcagaa tcacaccacc ccgaagagcc ccttcaccag atggcttctc accatatagc 900 cctgaggaaa caaaccgccg tgttaacaaa gtgatgcggg ccagactgta cttactgcag 960 cagatagggc ctaactcttt cctgattgga ggagacagcc cagacaataa ataccgggtg 1020 tttattgggc ctcagaactg cagctgtgca cgtggaacat tctgtattca tctgctattt 1080 gtgatgctcc gggtgtttca actagaacct tcagacccaa tgttatggag aaaaacttta 1140 aagaattttg aggttgagag tttgttccag aaatatcaca gtaggcgtag ctcaaggatc 1200 aaagctccat ctcgtaacac catccagaag tttgtttcac gcatgtcaaa ttctcataca 1260 ttgtcatcat ctagtacttc tacatctagt tcagaaaaca gcataaagga tgaagaggaa 1320 cagatgtgtc ctatttgctt gttgggcatg cttgatgaag aaagtcttac agtgtgtgaa 1380 gacggctgca ggaacaagct gcaccaccac tgcatgtcaa tttgggcaga agagtgtaga 1440 agaaatagag aacctttaat atgtcccctt tgtagatcta agtggagatc tcatgatttc 1500 tacagccacg agttgtcaag tcctgtggat tccccttctt ccctcagagc tgcacagcag 1560 caaaccgtac agcagcagcc tttggctgga tcacgaagga atcaagagag caattttaac 1620 cttactcatt atggaactca gcaaatccct cctgcttaca aagatttagc tgagccatgg 1680 attcaggtgt ttggaatgga actcgttggc tgcttatttt ctagaaactg gaatgtgaga 1740 gagatggccc tcaggcgtct ttcccatgat gtcagtgggg ccctgctgtt ggcaaatggg 1800 gagagcactg gaaattctgg gggcagcagt ggaagcagcc cgagtggggg agccaccagt 1860 gggtcttccc agaccagtat ctcaggagat gtggtggagg catgctgcag cgttctgtca 1920 atggtctgtg ctgaccctgt ctacaaagtg tacgttgctg ctttaaaaac attgagagcc 1980 atgctggtat atactccttg ccacagttta gcggaaagaa tcaaacttca gagacttctc 2040 cagccagttg tagacaccat cctagtcaaa tgtgcagatg ccaatagccg cacaagtcag 2100 ctgtccatat caacactgtt ggaactgtgc aaaggccaag caggagagtt ggcagttggc 2160 agagaaatac taaaagctgg atccattggt attggtggtg ttgattatgt cttaaattgt 2220 attcttggaa accaaactga atcaaacaat tggcaagaac ttcttggccg cctttgtctt 2280 atagatagac tgttgttgga atttcctgct gaattttatc ctcatattgt cagtactgat 2340 gtttcacaag ctgagcctgt tgaaatcagg tataagaagc tgctgtccct cttaaccttt 2400 gctttgcagt ccattaataa ttcccactca atggttggca aactttccag aaggatctac 2460 ttgagttctg caagaatggt tactacagta ccccatgtgt tttcaaaact gttagaaatg 2520 ctgagtgttt ccagttccac tcacttcacc aggatgcgtc gccgtttgat ggctattaca 2580 gatgaggtgg aaattgccga agccatccag ttgggcgtag aagacacttt ggatggtcaa 2640 caggacagct tcttgcaggc atctgttccc aacaactatc tggaaaccac agagaacagt 2700 tcccctgagt gcacaatcca tttagagaaa actggaaaag gattatgtgc tacaaaattg 2760 agtgccagtt cagaggacat ttctgagaga ctggccagca tttcagtagg accttctagt 2820 tcaacaacaa caacaacaac aacagagcaa ccaaagccaa tggttcaaac aaaaggcaga 2880 ccccacagtc agtgtttgaa ctcctctcct ttatctcatc attcccaatt aatgtttcca 2940 gccttgtcaa ccccttcttc ttctacccca tctgtaccag ctggcactgc aacagatgtc 3000 tctaagcata gacttcaggg attcattccc tgcagaatac cttctgcatc tcctcaaaca 3060 cagcgcaagt tttctctaca attccacaga aactgtcctg aaaacaaaga ctcagataaa 3120 ctttccccag tctttactca gtcaagaccc ttgccctcca gtaacataca caggccaaag 3180 ccatctcgac ctaccccagg taatacaagt aaacagggag atccctcaaa aaatagcatg 3240 acacttgatc tgaacagtag ttccaaatgt gatgacagct ttggctgtag cagcaatagt 3300 agtaatgctg ttatacccag tgacgagaca gtgttcaccc cagtagagga gaaatgcaga 3360 ttagatgtca atacagagct caactccagt attgaggacc ttcttgaagc atctatgcct 3420 tcaagtgata caacagtaac ttttaagtca gaagttgctg tcctgtctcc tgaaaaggct 3480 gaaaatgatg atacctacaa agatgatgtg aatcataatc aaaagtgcaa agagaagatg 3540 gaagctgaag aagaagaagc tttagcaatt gccatggcaa tgtcagcgtc tcaggatgcc 3600 ctccccatag ttcctcagct gcaggttgaa aatggagaag atatcatcat tattcaacag 3660 gatacaccag agactctacc aggacatacc aaagcaaaac aaccgtatag agaagacact 3720 gaatggctga aaggtcaaca gataggcctt ggagcatttt cttcttgtta tcaggctcaa 3780 gatgtgggaa ctggaacttt aatggctgtt aaacaggtga cttatgtcag aaacacatct 3840 tctgagcaag aagaagtagt agaagcacta agagaagaga taagaatgat gagccatctg 3900 aatcatccaa acatcattag gatgttggga gccacgtgtg agaagagcaa ttacaatctc 3960 ttcattgaat ggatggcagg gggatcggtg gctcatttgc tgagtaaata tggagccttc 4020 aaagaatcag tagttattaa ctacactgaa cagttactcc gtggcctttc gtatctccat 4080 gaaaaccaaa tcattcacag agatgtcaaa ggtgccaatt tgctaattga cagcactggt 4140 cagagactaa gaattgcaga ttttggagct gcagccaggt tggcatcaaa aggaactggt 4200 gcaggagagt ttcagggaca attactgggg acaattgcat ttatggcacc tgaggtacta 4260 agaggtcaac agtatggaag gagctgtgat gtatggagtg ttggctgtgc tattatagaa 4320 atggcttgtg caaaaccacc atggaatgca gaaaaacact ccaatcatct tgctttgata 4380 tttaagattg ctagtgcaac tactgctcca tcgatccctt cacatttgtc tcctggttta 4440 cgagatgtgg ctcttcgttg tttagaactt caacctcagg acagacctcc atcaagagag 4500 ctactgaagc atccagtctt tcgtactaca tggtagccaa ttatgcagat caactacagt 4560 agaaacagga tgctcaacaa gagaaaaaaa acttgtgggg aaccacattg atattctact 4620 ggccatgatg ccactgaaca gctatgaacg aggccagtgg ggaaccctta cctaagtatg 4680 tggattgaca aatcatgatc tgtacctaag ctcagtatgc aaaagcccaa actagtgcag 4740 aaactgtaaa ctgtgccttt caagaactgg cctaagtgaa ccaggaaaac aatgaagttt 4800 gctgacttaa tttgaaagct attttttctc ctggaccctt tttcgaaaaa ttacgcta 4858 27 2903 DNA Homo sapiens misc_feature Incyte ID No 7482905CB1 27 tatgacgtcg cctgtacagc ggtaccgtga gcttcgagta gttcgtgcat ctgggaccgt 60 tattccatac taacgtcctg tgtcactgag ttttttaaat gtctagcata tctgtaaaga 120 tgccttagaa aaagaatcat ggagaagtat gttagactac agaagattgg agaaggttca 180 tttggaaaag ccattcttgt taaatctaca gaagatggca gacagtatgt tatcaaggaa 240 attaacatct caagaatgtc cagtaaagaa agagaaggct ggaatttatt gaaaaagaaa 300 agaaacaaaa ggatcagatt attagtttaa tgaaggctga acaaatgaaa aggcaagaaa 360 aggaaaggtt ggaaagaata aatagggcca gggaacaagg atggagaaat gtgctaagtg 420 ctggtggaag tggtgaagta aaggctcctt ttctgggcag tggagggact atagctccat 480 catctttttc ttctcgagga cagtatgaac attaccatgc catttttgac caaatgcagc 540 aacaaagagc agaagataat gaagctaaat ggaaaagaga aatatatggt cgaggtcttc 600 cagaaaggca aaaagggcag ctagctgtag aaagagctaa acaagtagaa gagttcctgc 660 agcgaaaacg ggaagctatg cagaataaag ctcgagccga aggacatatg gtttatctgg 720 caagactgag gcaaataaga ctacagaatt tcaatgagcg ccaacagatt aaagccaaac 780 ttcgtggtga aaagaaagaa gctaatcatt ctgaaggaca agaaggaagt gaagaggctg 840 acatgaggcg caaaaaaatc gaatcactga aggcccatgc aaatgcacgt gctgctgtac 900 taaaagaaca actagaacga aagagaaagg aggcttatga gagagaaaaa aaagtgtggg 960 aagagcattt ggtggctaaa ggagttaaga gttctgatgt ttctccacct ttgggacagc 1020 atgaaacagg tggctctcca tcaaagcaac agatgagatc tgttatttct gtaacttcag 1080 ctttgaaaga agttggcgtg gacagtagtt taactgatac ccgggaaact tcagaagaga 1140 tgcaaaagac caacaatgct atttcaagta agcgagaaat acttcgtaga ttaaatgaaa 1200 atcttaaagc tcaagaagat gaaaaaggaa agcagaatct ctctgatact tttgagataa 1260 atgttcatga agatgccaaa gagcatgaaa aagaaaaatc agtttcatct gatcgcaaga 1320 agtgggaggc aggaggtcaa cttgtgattc ctctggatga gttaacacta gatacatcct 1380 tctctacaac tgaaagacat acagtgggag aagttattaa attaggtcct aatggatctc 1440 caagaagagc ctgggggaaa agtccgacag attctgttct aaagatactt ggagaagctg 1500 aactacaact tcagacagaa ctattagaaa atacaactat tagaagtgag atttctcccg 1560 aaggggaaaa gtacaaaccc ttaattactg gagaaaaaaa agtacaatgt atttcacatg 1620 aaataaaccc atcagctatt gttgattctc ctgttgagac aaaaagtccc gagttcagtg 1680 aggcatctcc acagatgtca ttgaaactgg aaggaaattt agaagaacct gatgatttgg 1740 aaacagaaat tctacaagag ccaagtggaa caaacaaaga tgagagcttg ccatgcacta 1800 ttactgatgt gtggattagt gaggaaaaag aaacaaagga aactcagtcg gcagatagga 1860 tcaccattca ggaaaatgaa gtttctgaag atggagtctc gagtactgtg gaccaactta 1920 gtgacattca tatagagcct ggaaccaatg attctcagca ctctaaatgt gatgtagata 1980 agtctgtgca accggaacca tttttccata aggtggttca ttctgaacac ttgaacttag 2040 tccctcaagt tcaatcagtt cagtgttcac cagaagaatc ctttgcattt cgatctcact 2100 cgcatttacc accaaaaaat aaaaacaaga attccttgct gattggactt tcaactggtc 2160 tgtttgatgc aaacaaccca aagatgttaa ggacatgttc acttccagat ctctcaaagc 2220 tgttcagaac ccttatggat gttcccaccg taggagatgt tcgtcaagac aatcttgaaa 2280 tagatgaaat tgaagatgaa aacattaaag aaggaccttc tgattctgaa gacattgtgt 2340 ttgaagaaac tgacacagat ttacaagagc tgcaggcctc gatggaacag ttacttaggg 2400 aacaacctgg tgaagaatac agtgaagaag aagagtcagt cttgaagaac agtgatgtgg 2460 agccaactgc aaatgggaca gatgtggcag atgaagatga caatcccagc agtgaaagtg 2520 ccctgaacga agaatggcac tcagataaca gtgatggtga aattgctagt gaatgtgaat 2580 gcgatagtgt ctttaaccat ttagaggaac tgagacttca tctggagcag gaaatgggct 2640 ttgaaaaatt ctttgaggtt tatgagaaaa taaaggctat tcatgaagat gaagatgaaa 2700 atattgaaat ttgttcaaaa atagttcaaa atattttggg aaatgaacat cagcatcttt 2760 atgccaagat tcttcattta gtcatggcag atggagccta ccaagaagat aatgatgaat 2820 aatcctcaaa atgtttttta atcctcaact atatgaaagc atttgaattt ggcttatcag 2880 aataacagct tcagtgggag gcg 2903 28 1812 DNA Homo sapiens misc_feature Incyte ID No 7483019CB1 28 cttttccttc cctgtgccca ggccttgctc agtgcccatg acacgatagc tcagaaagat 60 tttgaacccc ttctccctcc actgccagac aatatccctg agagtgagga agcaatgagg 120 attgtttgtt tagtgaaaaa ccaacagccc ctgggagcca ccatcaagcg ccacgagatg 180 acaggggaca tcttggtggc caggatcatc cacggtgggc tggcggagag aagtgggttg 240 ctatatgctg gagacaaact ggtagaagtg aatggagttt cagttgaggg actggaccct 300 gaacaagtga tccatattct ggccatgtct cgaggcacaa tcatgttcaa ggtggttcca 360 gtctctgacc ctcctgtgaa tagccagcag atggtgtacg tccgtgccat gactgagtac 420 tggccccagg aggatcccga catcccctgc atggacgctg gattgccttt ccagaagggg 480 gacatcctcc agattgtgga ccagaatgat gccctctggt ggcaggcccg aaaaatctca 540 gaccctgcta cctgcgctgg gcttgtccct tctaaccacc ttctgaagag gaagcaacgg 600 gaattctggt ggtctcagcc gtaccagcct cacacctgcc tcaagtcaac cctatacaag 660 gaggagtttg ttggctacgg tcagaagttc tttatagctg gcttccgccg cagcatgcgc 720 ctttgtcgca ggaagtctca cctcagcccg ctgcatgcca gtgtgtgctg caccggcagc 780 tgctacagtg cagtgggtgc cccttacgag gaggtggtga ggtaccagcg acgcccttca 840 gacaagtacc gcctcatagt gctcatggga ccctctggtg ttggagtaaa tgagctcaga 900 agacaactta ttgaatttaa tcccagccat tttcaaagtg ctgtgccaca cactactcgt 960 actaaaaaga gttacgaaac gaatgggcgt gagtatcact atgtgtccaa ggaaacattt 1020 gaaaacctca tatatagtca caggatgctg gagtatggtg agtacaaagg ccacctgtat 1080 ggcactagtg tgggtgctgt tcaaacagtc cttgtcgaag gaaagatctg tgtcatggac 1140 ctagagcctc aggatattca aggggttcga acccatgaac tgaagcccta tgtcatattt 1200 ataaagccat cgaatatgag gtgtatgaaa caatctcgga aaaatgccaa ggttattact 1260 gactactatg tggacatgaa gttcaaggat gaagacctac aagagatgga aaatttagcc 1320 caaagaatgg aaactcagtt tggccaattt tttgatcatg tgattgtgaa tgacagcttg 1380 cacgatgcat gtgcccagtt gttgtctgcc atacagaagg ctcaggagga gcctcagtgg 1440 gtaccagcaa catggatttc ctcagatact gagtctcaat gagacttctt gtttaatgct 1500 ggagttttaa cactgtaccc ttgatacagc gatccatagt tgcaatctaa aacaacagta 1560 tttgacccat tttaatgtgt acaactttaa aagtgcagca atttattaat taatcttatt 1620 tgaaaaaaat ttttattgta tggttatgtg gttacctatt ttaacttaat tttttttcct 1680 ttacctcata tgcagctgtg gtagaaatat gaataatgtt aggtcactga gtatgagaac 1740 ctttcgcaga tttcacatga tctttttaag atttaaataa agagctttcc taaataaaaa 1800 aaaaaaaaaa gg 1812 29 5480 DNA Homo sapiens misc_feature Incyte ID No 5455490CB1 29 ggtgtttcgg aagatcatgt tttttgaaga aaagtactta attttttgcc gtaagtttgg 60 gaagctttta taaatttcct ttggctgaca gaactgcata ccccttgtgt gagagaactt 120 cctaccaaga ctccagtgtg agggcaaaaa cttgagtagc caggagaatg atgaaacgga 180 ggcgagagag actgggagca ccatgtctgc ggattcaaat ctctactctt tgccgaggag 240 ctgaagtaaa ccagcacatg ttttcaccca catctgctcc agccctcttc ctcactaaag 300 tcccatttag tgctgattgt gctttggcta cttctcctct tgccattttc ctgaacccac 360 gagcccacag cagtcctggc actccttgtt ccagccgccc actgccgtgg agttgtcgga 420 caagtaaccg caagagcttg attgtgacct ctagcacatc acctacacta ccacggccac 480 actcaccact ccatggccac acaggtaaca gtcctttgga cagcccccgg aatttctctc 540 caaatgcacc tgctcacttt tcttttgttc ctgcccgtag ccatagccac agagctgaca 600 ggactgatgg gcggcgctgg tctttggcct ctttgccctc ttcaggatat ggaactaaca 660 ctcctagctc cactgtctca tcatcatgct cctcacagga aaagctgcat cagttgcctt 720 tccagcctac agctgatgag ctgcactttt tgacgaagca tttcagcaca gagagcgtac 780 cagatgagga aggacggcag tccccagcca tgcggcctcg ctcccggagc ctcagtcccg 840 gacgatcccc agtatccttt gacagtgaaa taataatgat gaatcatgtt tacaaagaaa 900 gattcccaaa ggccaccgca caaatggaag agcgactagc agagtttatt tcctccaaca 960 ctccagacag cgtgctgccc ttggcagatg gagccctgag ctttattcat catcaggtga 1020 ttgagatggc ccgagactgc ctggataaat ctcggagtgg cctcattaca tcacaatact 1080 tctacgaact tcaagagaat ttggagaaac ttttacaaga tgctcatgag cgctcagaga 1140 gctcagaagt ggcttttgtg atgcagctgg tgaaaaagct gatgattatc attgcccgcc 1200 cagcacgtct cctggaatgc ctggagtttg accctgaaga gttctaccac cttttagaag 1260 cagctgaggg ccacgccaaa gagggacaag ggattaaatg tgacattccc cgctacatcg 1320 ttagccagct gggcctcacc cgggatcccc tagaagaaat ggcccagttg agcagctgtg 1380 acagtcctga cactccagag acagatgatt ctattgaggg ccatggggca tctctgccat 1440 ctaaaaagac accctctgaa gaggacttcg agaccattaa gctcatcagc aatggcgcct 1500 atggggctgt atttctggtg cggcacaagt ccacccggca gcgctttgcc atgaagaaga 1560 tcaacaagca gaacctgatc ctacggaacc agatccagca ggccttcgtg gagcgtgaca 1620 tactgacttt cgctgagaac ccctttgtgg tcagcatgtt ctgctccttt gataccaagc 1680 gccacttgtg catggtgatg gagtacgttg aagggggaga ctgtgccact ctgctgaaga 1740 atattggggc cctgcctgtg gacatggtgc gtctatactt tgcggaaact gtgctggccc 1800 tggagtactt acacaactat ggcatcgtgc accgtgacct caagcctgac aacctcctaa 1860 ttacatccat ggggcacatc aagctcacgg actttggact gtccaaaatt ggcctcatga 1920 gtctgacaac gaacttgtat gagggtcata ttgaaaagga tgcccgggaa ttcctggaca 1980 agcaggtatg cgggacccca gaatacattg cgcctgaggt gatcctgcgc cagggctatg 2040 ggaagccagt ggactggtgg gccatgggca ttatcctgta tgagttcctg gtgggctgcg 2100 tccctttttt tggagatact ccggaggagc tctttgggca ggtgatcagt gatgagattg 2160 tgtggcctga gggtgatgag gcactgcccc cagacgccca ggacctcacc tccaaactgc 2220 tccaccagaa ccctctggag agacttggca caggcagtgc ctatgaggtg aagcagcacc 2280 cattctttac tggtctggac tggacaggac ttctccgcca gaaggctgaa tttattcctc 2340 agttggagtc agaggatgat actagctatt ttgacacccg ctcagagcga taccaccaca 2400 tggactcgga ggatgaggaa gaagtgagtg aggatggctg ccttgagatc cgccagttct 2460 cttcctgctc tccaaggttc aacaaggtgt acagcagcat ggagcggctc tcactgctcg 2520 aggagcgccg gacaccaccc ccgaccaagc gcagcctgag tgaggagaag gaggaccatt 2580 cagatggcct ggcagggctc aaaggccgag accggagctg ggtgattggc tcccctgaga 2640 tattacggaa gcggctgtcg gtgtctgagt catcccacac agagagtgac tcaagccctc 2700 caatgacagt gcgacgccgc tgctcaggcc tcctggatgc gcctcggttc ccggagggcc 2760 ctgaggaggc cagcagcacc ctcaggaggc aaccacagga gggtatatgg gtcctgacac 2820 ccccatctgg agagggggta tctgggcctg tcactgaaca ctcaggggag cagcggccaa 2880 agctggatga ggaagctgtt ggccggagca gtggttccag tccagctatg gagacccgag 2940 gccgtgggac ctcacagctg gctgagggag ccacagccaa ggccatcagt gacctggctg 3000 tgcgtagggc ccgccaccgg ctgctctctg gggactcaac agagaagcgc actgctcgcc 3060 ctgtcaacaa agtgatcaag tccgcctcag ccacagccct ctcactcctc attccttcgg 3120 aacaccacac ctgctccccg ttggccagcc ccatgtcccc acattctcag tcgtccaacc 3180 catcatcccg ggactcttct ccaagcaggg acttcttgcc agcccttggc agcatgaggc 3240 ctcccatcat catccaccga gctggcaaga agtatggctt caccctgcgg gccattcgcg 3300 tctacatggg tgactccgat gtctacaccg tgcaccatat ggtgtggcac gtggaggatg 3360 gaggtccggc cagtgaggca gggcttcgtc aaggtgacct catcacccat gtcaatgggg 3420 aacctgtgca tggcctggtg cacacggagg tggtagagct gatcctgaag agtggaaaca 3480 aggtggccat ttcaacaact cccctggaga acacatccat taaagtgggg ccagctcgga 3540 agggcagcta caaggccaag atggcccgaa ggagcaagag gagccgcggc aaggatgggc 3600 aagaaagcag aaaaaggagc tccctgttcc gcaagatcac caagcaagca tccctgctcc 3660 acaccagccg cagcctttcc tcccttaacc gctccttgtc atcaggggag agtgggccag 3720 gctctcccac acacagccac agcctttccc cccgatctcc cactcaaggc taccgggtga 3780 cccccgatgc tgtgcattca gtgggaggga attcatcaca gagcagctcc cccagctcca 3840 gcgtgcccag ttccccagcc ggctctgggc acacacggcc cagctccctc cacggtctgg 3900 cacccaagct ccaacgccag taccgctctc cacggcgcaa gtcagcaggc agcatcccac 3960 tgtcaccact ggcccacacc ccttctcccc cacccccaac agcttcacct cagcggtccc 4020 catcgcccct gtctggccat gtagcccagg cctttcccac aaagcttcac ttgtcacctc 4080 ccctgggcag gcaactctca cggcccaaga gtgcggagcc accccgttca ccactactca 4140 agagggtgca gtcggctgag aaactggcag cagcacttgc cgcctctgag aagaagctag 4200 ccacttctcg caagcacagc cttgacctgc cccactctga actaaagaag gaactgccgc 4260 ccagggaagt gagccctctg gaggtagttg gagccaggag tgtgctgtct ggcaaggggg 4320 ccctgccagg gaagggggtg ctgcagcctg ctccctcacg ggccctaggc accctccggc 4380 aggaccgagc cgaacgacgg gagtcgctgc agaagcaaga agccattcgt gaggtggact 4440 cctcagagga cgacaccgag gaagggcctg agaacagcca gggtgcacag gagctgagct 4500 tggcacctca cccagaagtg agccagagtg tggcccctaa aggagcagga gagagtgggg 4560 aagaggatcc tttcccgtcc agagacccta ggagcctggg cccaatggtc ccaagcctat 4620 tgacagggat cacactgggg cctcccagaa tggaaagtcc cagtggtccc cacaggaggc 4680 tcgggagccc acaagccatt gaggaggctg ccagctcctc ctcagcaggc cccaacctag 4740 gtcagtctgg agccacagac cccatccctc ctgaaggttg ctggaaggcc cagcacctcc 4800 acacccaggc actaacagca ctttctccca gcacttcggg actcaccccc accagcagtt 4860 gctctcctcc cagctccacc tctgggaagc tgagcatgtg gtcctggaaa tcccttattg 4920 agggcccaga cagggcatcc ccaagcagaa aggcaaccat ggcaggtggg ctagccaacc 4980 tccaggattt ggaaaacaca actccagccc agcctaagaa cctgtctccc agggagcagg 5040 ggaagacaca gccacctagt gcccccagac tggcccatcc atcttatgag gatcccagcc 5100 agggctggct atgggagtct gagtgtgcac aagcagtgaa agaggatcca gccctgagca 5160 tcacccaagt gcctgatgcc tcaggtgaca gaaggcagga cgttccatgc cgaggctgcc 5220 ccctcaccca gaagtctgag cccagcctca ggaggggcca agaaccaggg ggccatcaaa 5280 agcatcggga tttggcattg gttccagatg agcttttaaa gcaaacatag cagttgtttg 5340 ccatttcttg cactcagacc tgtgtaatat atgctcctgg aaaccatctt tatgtctttt 5400 gcttgcttgt tttccttcgg tcaacccaca tgtaactagg tcctgtgttg ctgctgggaa 5460 tatagtggtg aataaagcat 5480 30 1568 DNA Homo sapiens misc_feature Incyte ID No 5547067CB1 30 caggaaaaaa agatatttta aatttgatgc tcatttttgt gtgtgtgtgt tgagtgcatg 60 cattcaatct gtgtattcct ccctcatcaa cccagaacat cctgcagctg ccactctgag 120 ggtggcccct tccttcctct gccctgaagc tgtatcacag agatttctag tcctagtgtg 180 actctggccc catgctgatg ggtttctgca gactggaaga ggcggggctc gtgtcacgca 240 gcatcaggga gaggaattgc ttatataact gggacagcag atttagcaga gagaggaggc 300 agaggctggg aatgggagca gtaagctgtc ggcaggggca gcacacccag cagggggaac 360 acacccgggt ggctgtccct cacaagggtg gcaacatccg gggtccctgg gcccgaggct 420 ggaagagcct ctggacaggt ttgggaacca tcaggtcaga tctggaagaa ctctgggaac 480 tacgggggca ccactatctg caccaggaat ccctaaagcc agccccagta ctggtagaga 540 agcctctgcc agagtggcca gtgcctcagt tcatcaacct ctttctacca gagtttccca 600 ttaggcccat tagggggcag cagcagctga agattttagg cctcgtggct aaaggctcct 660 ttggaactgt cctcaaggtg ctagattgca cccagaaagc tgtatttgca gtgaaggtgg 720 tgcccaaggt aaaggtccta cagagggata ccgtgaggca gtgcaaagag gaggttagca 780 tccagcgaca gatcaaccat ccctttgtac acagcttggg ggacagctgg cagggaaaac 840 ggcacctttt cattatgtgt agctactgca gcacagatct gtactccctt tggtcggctg 900 ttggctgctt tcctgaggct tccatccgtc tctttgctgc cgagttggtg ctggtactgt 960 gttatctcca tgacttgggc atcatgcatc gagatgtgaa gatggagaat attcttctag 1020 atgaacgagg ccatctgaaa ctgacagact ttggtctgtc ccgccacgtg ccccagggag 1080 ctcaagccta cactatctgt ggcactcttc agtacatggc cccagaggtc ctaagtggag 1140 gaccttacaa ccatgctgct gattggtggt ccctgggtgt cttgcttttc tctctggcga 1200 ctggaaagtt tccagtggct gcagagagag atcatgtggc catgttggca agtgtgaccc 1260 acagtgactc tgagatccca gcttctctta accagggcct ctcactcctg ctccatgagc 1320 tcttatgcca gaaccccctc catcgtctac gttatctgca tcacttccag gtccaccctt 1380 tctttcgggg tgtggccttc gacccagagc tcctacagaa gcagccagtg aactttgtca 1440 cggagacaca agctacccag cccagttcag cggagaccat gccctttgac gactttgact 1500 gtgatctgga gtccttcttg ctctacccta tccctgcttg agcctctcta ctgtaaattg 1560 gggcccgg 1568 31 2365 DNA Homo sapiens misc_feature Incyte ID No 71675660CB1 31 cccctttttt tttttttcta ggaaagaagg gagtttatca ctgtaactgg atacagggag 60 aaggctggag ataattccag cagaccaact caaagtgcta caattttctt actgtttata 120 taggttgggg ttatgtgcct acatgcagta cagcaatcac ctaagtctac tggtaactaa 180 ttttgttcca aggagaaggt cagaggcaaa aaaaatgctt gctaagtccg attaaaaggg 240 gcccagtgcc ttcaaggcct gtctactgtg gtaccggagt gattatttcg attgtatctc 300 ctttacagct tggtccagag agctgcctta gactatccaa ttgatctatt caaacagctg 360 cctgttccct taacttgtct tcagattttg tcgacccgag atgggtcctg gcactaggaa 420 tgtaaaaccg ttcctattat tttggcttgc tccagcaaaa gagaagccca tgcaaggctc 480 ctgctgacca tgtttcattt ctagctttga tgtctgggca ctgatttccc tagatttaac 540 tatgtgctca atggtaaggc agtgctgtgg aaatctgtct gtgtaactgg ggtgctatgc 600 aggcctgtct gggtgactgt cagggacaac tgtcctacca caccaaggac acagccctgg 660 gggtgctttt cttcatagcc aaagaagctg caggaaaccc accctagtgg gacaaagacc 720 aatgcagggt cagtccccac agccaggtga tgcaaacagg ctggacgtgg gccgcctccc 780 ctccagcttg acttgtgaca gggaaaccaa tgcagcagca gcagggccac cagagtcctg 840 tcctggggac aggcttcctt ccagcgggcg gggagtgggt gctcctgcca gaccagcctg 900 gcttccacgg ttccagagac cctgttcccc ctcagcccag tccccgcccc cactccttgg 960 ctttatgagt tcattggctg aagtcacccg gagacaatgc tgagtgttcc acccctgagt 1020 cgaagcccag cccagggcag cccagccaga cgcctccggt agtgtaaatg aggacaatgc 1080 ctgctggccc acatgacggg gggatgtaga cggcagcggc gccagtcgct cctggcacca 1140 tggacgatgc cacagtccta aggaagaagg gttacatcgt aggcatcaat cttggcaagg 1200 gttcctacgc aaaagtcaaa tctgcctact ctgagcgcct caagttcaat gtggctgtca 1260 agatcatcga ccgcaagaaa acacctactg actttgtgga gagattcctt cctcgggaga 1320 tggacatcct ggcaactgtc aaccacggct ccatcatcaa gacttacgag atctttgaga 1380 cctctgacgg acggatctac atcatcatgg agcttggcgt ccagggcgac ctcctcgagt 1440 tcatcaagtg ccagggagcc ctgcatgagg acgtggcacg caagatgttc cgacagctct 1500 cctccgccgt caagtactgc cacgacctgg acatcgtcca ccgggacctc aagtgcgaga 1560 accttctcct cgacaaggac ttcaacatca agctgtctga ctttggcttc tccaagcgct 1620 gcctgcggga cagcaatggg cgcatcatcc tcagcaagac cttctgcggg tcggcagcat 1680 atgcagcccc cgaggtgctg cagagcatcc cctaccagcc caaggtgtat gacatctgga 1740 gcctgggcgt gatcctgtac atcatggtct gtggctccat gccctatgac gactccgaca 1800 tcaggaagat gctgcgtatc cagaaggagc accgtgtgga cttcccgcgc tccaagaacc 1860 tgacctgcga gtgcaaggac ctcatctacc gcatgctgca gcccgacgtc agtcagcggc 1920 tccacatcga tgagatcctc agccactcgt ggctgcagcc ccccaagccc aaagccatgt 1980 cttctgcctc cttcaagagg gagggggagg gcaagtaccg cgctgagtgc aaactggaca 2040 ccaagacagg cttgaggccc gaccaccggc ccgaccacaa gcttggagcc aaaacccagc 2100 accggctgct ggtggtgccc gagaacgaga acaggatgga ggacaggctg gccgagacct 2160 ccagagccaa agaccatcac atctccggag ctgaggtggg gaaagcaagc acctagcatg 2220 acaatggccc cgttgtgtgt ggtgggggtc ggggttgggg ggcatggtgc agtcggcctt 2280 cacgtaaact aagtaggcag gtaggatctg aagaaggcac aggtgcaagt aaaattcgtc 2340 aattaaacca ctattttgat taaaa 2365 32 2626 DNA Homo sapiens misc_feature Incyte ID No 71678683CB1 32 cccctttttt tttttttcta ggaaagaagg gagtttatca ctgtaactgg atacagggag 60 aaggctggag ataattccag cagaccaact caaagtgcta caattttctt actgtttata 120 taggttgggg ttatgtgcct acatgcagta cagcaatcac ctaagtctac tggtaactaa 180 ttttgttcca aggagaaggt cagaggcaaa aaaaatgctt gctaagtccg attaaaaggg 240 gcccagtgcc ttcaaggcct gtctactgtg gtaccggagt gattatttcg attgtatctc 300 ctttacagct tggtccagag agctgcctta gactatccaa ttgatctatt caaacagctg 360 cctgttccct taacttgtct tcagattttg tcgacccgag atgggtcctg gcactaggaa 420 tgtaaaaccg ttcctattat tttggcttgc tccagcaaaa gagaagccca tgcaaggctc 480 ctgctgacca tgtttcattt ctagctttga tgtctgggca ctgatttccc tagatttaac 540 tatgtgctca atggtaaggc agtgctgtgg aaatctgtct gtgtaactgg ggtgctatgc 600 aggcctgtct gggtgactgt cagggacaac tgtcctacca caccaaggac acagccctgg 660 gggtgctttt cttcatagcc aaagaagctg caggaaaccc accctagtgg gacaaagacc 720 aatgcagggt cagtccccac agccaggtga tgcaaacagg ctggacgtgg gccgcctccc 780 ctccagcttg acttgtgaca gggaaaccaa tgcagcagca gcagggccac cagagtcctg 840 tcctggggac aggcttcctt ccagcgggcg gggagtgggt gctcctgcca gaccagcctg 900 gcttccacgg ttccagagac cctgttcccc ctcagcccag tccccgcccc cactccttgg 960 ctttatgagt tcattggctg aagtcacccg gagacaatgc tgagtgttcc acccctgagt 1020 cgaagcccag cccagggcag cccagccaga cgcctccggt agtgtaaatg aggacaatgc 1080 ctgctggccc acatgacggg gggatgtaga cggcagcggc gccagtcgct cctggcacca 1140 tggacgatgc cacagtccta aggaagaagg gttacatcgt aggcatcaat cttggcaagg 1200 gttcctacgc aaaagtcaaa tctgcctact ctgagcgcct caagttcaat gtggctgtca 1260 agatcatcga ccgcaagaaa acacctactg actttgtgga gagattcctt cctcgggaga 1320 tggacatcct ggcaactgtc aaccacggct ccatcatcaa gacttacgag atctttgaga 1380 cctctgacgg acggatctac atcatcatgg agcttggcgt ccagggcgac ctcctcgagt 1440 tcatcaagtg ccagggagcc ctgcatgagg acgtggcacg caagatgttc cgacagctct 1500 cctccgccgt caagtactgc cacgacctgg acatcgtcca ccgggacctc aagtgcgaga 1560 accttctcct cgacaaggac ttcaacatca agctgtctga ctttggcttc tccaagcgct 1620 gcctgcggga cagcaatggg cgcatcatcc tcagcaagac cttctgcggg tcggcagcat 1680 atgcagcccc cgaggtgctg cagagcatcc cctaccagcc caaggtgtat gacatctgga 1740 gcctgggcgt gatcctgtac atcatggtct gcggctccat gccctatgac gactccgaca 1800 tcaggaagat gctgcgtatc cagaaggagc accgtgtgga cttcccgcgc tccaagaacc 1860 tgacctgcga gtgcaaggac ctcatctacc gcatgctgca gcccgacgtc agccagcggc 1920 tccacatcga tgagatcctc agccactcgt ggctgcagcc ccccaagccc aaagccacgt 1980 cttctgcctc cttcaagagg gagggggagg gcaagtaccg cgctgagtgc aaactggaca 2040 ccaagacagg cttgaggccc gaccaccggc ccgaccacaa gcttggagcc aaaacccagc 2100 accggctgct ggtggtgccc gagaacgaga acaggatgga ggacaggctg gccgagacct 2160 ccagggccaa agaccatcac atctccggag ctgaggtggg gaaagcaagc acctagcatg 2220 acaatggccc cgttgtgtgt ggtgggggtc ggggttgggg ggcatggtgc agtcggcctt 2280 cacgtaaact aagtaggcag gtaggatctg aagaaggcac aggtgcaagt aaaattcgtc 2340 aattaaacca ctattttgat tacgttccat tagctttctt ccacttagca gcaaagacgt 2400 tccttactga ccaccaaata aaccacaggg tgtgtgcaag catcaagagt gcccagtgag 2460 gagtgttttt ctctgggact cagccaaccg ccccacctga cacacagtgg tctccggcct 2520 aggagcacag gacagatgct caggtacagg cagaatcaca gtgtggcctg gccttgtggg 2580 ggacaagagg gcctctgcca gggtccaccc accaggccca cactgt 2626 33 3961 DNA Homo sapiens misc_feature Incyte ID No 7474567CB1 33 ccctgtaata cgaactcact atagggcgac cagtgtgctg gaaagcggcc gcgggggcgg 60 cggaggatat ggagtaaagc cagagtcagt ggccaggcac gaaggcagag caggaacagc 120 caggaggcgt ttattagggg ggcgggggga aagagcccca gcaccgcccc tcctggaaga 180 aggaagaggt aactataact acccaatatt gcagccatgg agtccatgct taataaattg 240 aagagtactg ttacaaaagt aacagctgat gtcactagtg ctgtaatggg aaatcctgtc 300 actagagaat ttgatgttgg tcgacacatt gccagtggtg gcaatgggct agcttggaag 360 atttttaatg gcacaaaaaa gtcaacaaag caggaagtgg cagtttttgt ctttgataaa 420 aaactgattg acaagtatca aaaatttgaa aaggatcaaa tcattgattc tctaaaacga 480 ggagtccaac agttaactcg gcttcgacac cctcgacttc ttactgtcca gcatccttta 540 gaagaatcca gggattgctt ggcattttgt acagaaccag tttttgccag tttagccaat 600 gttcttggta actgggaaaa tctaccttcc cctatatctc cagacattaa ggattataaa 660 ctttatgatg tagaaaccaa atatggtttg cttcaggttt ctgaaggatt gtcattcttg 720 catagcagtg tgaaaatggt gcatggaaat atcactcctg aaaatataat tttgaataaa 780 agtggagcct ggaaaataat gggttttgat ttttgtgtat catcaaccaa tccttctgaa 840 caagagccta aatttccttg taaagaatgg gacccaaatt taccttcatt gtgtcttcca 900 aatcctgaat atttggctcc tgaatacata ctttctgtga gctgtgaaac agccagtgat 960 atgtattctt taggaactgt tatgtatgct gtatttaata aagggaaacc tatatttgaa 1020 gtcaacaagc aagatattta caagagtttc agtaggcagt tggatcagtt gagtcgttta 1080 ggatctagtt cacttacaaa tatacctgag gaagttcgtg aacatgtaaa gctactgtta 1140 aatgtaactc cgactgtaag accagatgca gatcaaatga caaagattcc cttctttgat 1200 gatgttggtg cagtaacact gcaatatttt gataccttat tccaaagaga taatcttcag 1260 aaatcacagt ttttcaaagg actgccaaag gttctaccaa aactgcccaa gcgtgtcatt 1320 gtgcagagaa ttttgccttg tttgacttca gaatttgtaa accctgacat ggtacctttt 1380 gttttgccca atgttctact tattgctgag gaatgcacca aagaagaata tgtcaaatta 1440 attcttcctg aacttggccc tgtgtttaag cagcaggagc caatccagat tttgttaatt 1500 ttcctacaaa aaatggattt gctactaacc aaaacccctc ctgatgagat aaagaacagt 1560 gttctaccca tggtttacag agcactagaa gctccttcca ttcagatcca ggagctctgt 1620 ctaaacatca ttccaacctt tgcaaatctt atagactacc catccatgaa aaacgctttg 1680 ataccaagaa ttaaaaatgc ttgtctacaa acatcttccc ttgcggttcg tgtaaattca 1740 ttagtgtgct taggaaagat tttggaatac ttggataagt ggtttgtact tgatgatatc 1800 ctacccttct tacaacaaat tccatccaag gaacctgcgg tcctcatggg aattttaggt 1860 atttacaaat gtacttttac tcataagaag ttgggaatca ccaaagagca gctggccgga 1920 aaagtgttgc ctcatcttat tcccctgagt attgaaaaca atcttaatct taatcagttc 1980 aattctttca tttccgtcat aaaagaaatg cttaatagat tggagtctga acataagact 2040 aaactggagc aacttcatat aatgcaagaa cagcagaaat ctttggatat aggaaatcaa 2100 atgaatgttt ctgaggagat gaaagttaca aatattggga atcagcaaat tgacaaagtt 2160 tttaacaaca ttggagcaga ccttctgact ggcagtgagt ccgaaaataa agaggacggg 2220 ttacagaata aacataaaag agcatcactt acacttgaag aaaaacaaaa attagcaaaa 2280 gaacaagagc aggcacagaa gctgaaaagc cagcagcctc ttaaacccca agtgcacaca 2340 cctgttgcta ctgttaaaca gactaaggac ttgacagaca cactgatgga taatatgtca 2400 tccttgacca gcctttctgt tagtacccct aaatcttctg cttcaagtac tttcacttct 2460 gttccttcca tgggcattgg tatgatgttt tctacaccaa ctgataatac aaagagaaat 2520 ttgacaaatg gcctaaatgc caatatgggc tttcagactt caggattcaa catgcccgtt 2580 aatacaaacc agaacttcta cagtagtcca agcacagttg gagtgaccaa gatgactctg 2640 ggaacacctc ccactttgcc aaacttcaat gctttgagtg ttcctcctgc tggtgcaaag 2700 cagacccaac aaagacccac agatatgtct gcccttaata atctctttgg ccctcagaaa 2760 cccaaagtta gcatgaacca gttatcacaa cagaaaccaa atcagtggct taatcagttt 2820 gtacctcctc aaggttctcc aactatgggc agttcagtaa tggggacaca gatgaacgtg 2880 ataggacaat ctgcttttgg tatgcagggt aatcctttct ttaacccaca gaactttgca 2940 cagccaccaa ctactatgac caatagcagt tcagctagca atgatttaaa agatcttttt 3000 gggtgaggtg tcttacttct attttgaagg attatttcag tttcaatcat gggtgagctg 3060 atttacatct ttatatagtt ggcttggagg aagtacttct atgggaaagt gaacagttct 3120 gtgacaggaa acatctctgt ccatgccagc atagtagttg tatggacttc taaccagttg 3180 agttttttaa agcattgagg attttttcct cttaccaact cctcttcagg tttttaaaga 3240 cccagccctt cccaatctca aagagaaaaa ggaaactgag ttatcttgaa taacataact 3300 ttttaatcaa atgtttattt tggcttgtgg atcttggtgt tatttaaaaa attgaggtga 3360 tggtcattgc aagctcatct attaagtact atatggtaca cagtctatga gtcattagtc 3420 ttcattttaa tatgtaaaaa atcttgatgc tgtattgatt tgtttgcatt taagatgaca 3480 gtgagaaaat gataagcata aagagaagta tcaggttatt tgctttttcc aaacttttca 3540 gatgaactat tgtttagtac agagactgag caaatactac aaaattcaac ttaaccttca 3600 tttcattggt ttaaatgcgt tattaaccat cttaagtgca aactaatcat tgtaaattat 3660 attttagcat ggtctgcctc aaatagtaat gtatttttct gcattcactt ggatatattt 3720 agaatcactt ttttcctcct gtatcaagga agaggtatgt gctgatttgt ttggatattt 3780 gacaaggcac tctgatgtga cttccctgac tactaccttc atatttcatt tcaaattcaa 3840 acttctgagg ttgcagcata tatgaattgc attttcaaaa gaagatttgt aagaattaaa 3900 ctatatttat gagtaaactt ttgaggtttc tgctgtattg tttcaaatgt aataaacttt 3960 a 3961 34 2210 DNA Homo sapiens misc_feature Incyte ID No 3838946CB1 34 ccagagggcc ggcatgtggt ctgcagaaga ggaggacgtg gctgggtggc agggctggtc 60 tccaaggacg agtaagatcc tgcagctgca ggcttcagga agtctcctgg ggctatcaga 120 tggctccttc ttgtagcagc agctgtgggg tccactggcc ctgagccctc agaggggcgg 180 ccgtggggga cctcctgtct tttgccttgc aagggcctca gttgtgcttt ttccctctag 240 gcagccatgg gtgccaggca gtgctgagag cagtggggca tggctgcagc cctgcaggtc 300 ctgccccgct tggcccgagc ccccttgcat ccactcctct ggcggggctc agtggcccgt 360 ctggccagca gcatggcctt ggcagagcag gccaggcagc tgtttgagag tgctgtaggt 420 gcagtgctgc cgggccccat gctgcaccgg gcactatcct tggaccctgg tggcagacag 480 ctgaaggtgc gggaccggaa ctttcagctg aggcaaaacc tctacctggt gggctttggc 540 aaggctgtgc tgggtatggc agctgcagct gaggaactac tgggccagca tcttgtgcag 600 ggcgtgatca gcgttcccaa ggggatccgt gctgccatgg agcgtgccgg caagcaggag 660 atgctgctga agccacatag ccgtgtccag gtattcgagg gtgcggagga caacctcccg 720 gaccgcgatg cgctgcgggc tgcactggcc atccagcaac tggctgaggg actcacagct 780 gatgacctgc tgctcgtgct gatctcaggt gggggttcag ctctgctgcc tgcccccatc 840 ccacctgtca cactggagga gaagcagaca ctcactagac tgctggcagc ccgtggagcc 900 accatccagg agttgaacac cattcggaag gccctgtccc agctcaaggg tggggggctg 960 gctcaggccg cctaccctgc ccaggtggtg agcctcatcc tgtcagatgt ggtgggggac 1020 cctgtggagg tgattgccag tggccccacc gtggccagtt cccacaatgt gcaagattgc 1080 ctgcatatcc tcaatcgcta cggcctccgt gcagccctgc cacgttctgt gaagactgtg 1140 ctgtctcggg ccgactctga cccccatggg ccacacacct gtggccatgt cctgaatgtg 1200 atcattggct ctaatgtgct ggcgctagct gaggcccagc ggcaggccga ggcactgggc 1260 taccaggctg tggtgctgag tgcagccatg caaggtgatg taaaaagtat ggcccagttc 1320 tacgggctgc tggcccatgt ggctagaacc cgcctcaccc catccatggc tggggcttct 1380 gtggaggaag atgcacagct ccatgagctg gcagctgagc ttcagatccc agacctgcag 1440 ctggaggagg ctctggagac catggcatgg ggaaggggcc cagtctgcct gctggctggt 1500 ggcgagccca cagtacagct gcagggctcg ggcaggggtg gccggaacca ggaactggcc 1560 ctgcgtgttg gagcagagtt gagaaggtgg ccgctggggc cgatagatgt gctgtttttg 1620 agcggtggca ccgatgggca ggatgggccc acagaggctg ctggggcctg ggtcacacct 1680 gagcttgcca gccaggctgc agctgagggc ctggacatag ccaccttcct agcccacaat 1740 gactcacata ccttcttctg ctgcctccag ggtggggcac acctgctgca cacagggatg 1800 acaggtacca atgtcatgga cacccacctc ttgttcctgc ggcctcggtg atggcatagg 1860 tcacattttg ggagttcaga ggaggcctac aagggcaagg tcagatggca gagcaaggtt 1920 ggtcctcagg gcctctctaa gccttagggc ccctcctctc cttggccttg gctgtttggt 1980 taactgtcac cttccactca gggcctctgc tctatatcta ttcccttcca gccagactgg 2040 cagatggggg cttcccccta cccctgagga tgaggacaag cccctcggcc agttcagcgt 2100 tcccgtgctt ctcccttggg cagcctctct cttgagcccc tcaccctgtt tctttctgtg 2160 aagcgagaat gtctgaaaat aaataggacc atgccaaaaa aaaaaaaaaa 2210 35 4869 DNA Homo sapiens misc_feature Incyte ID No 72001176CB1 35 ctgcgcttct cgcgaaacgg caggcatcgc ggggctggcc acttccgtac ttccgctttc 60 cggcccagcc agcgcccgcg atgactgcca ctctccgccc ctacctgagt gccgtgcggg 120 ccacattgca ggctgccctc tgcctggaga acttctcctc ccaggttgtg gaacgacaca 180 acaagccgga agtggaagtc aggagtagca aagagctcct gttacaacct gtgaccatca 240 gcaggaatga gaaggaaaag gttctgattg agggctccat caactctgtc cgggtcagca 300 ttgctgtgaa acaggctgat gagatcgaga agattttgtg ccacaagttc atgcgcttca 360 tgatgatgcg agcagagaac ttctttatcc ttcgaaggaa gcctgtggag gggtatgata 420 tcagctttct gatcaccaac ttccacacag agcagatgta caaacacaag ttggtggact 480 ttgtgatcca cttcatggag gagattgaca aggagatcag tgagatgaag ctgtcagtca 540 atgcccgtgc ccgcattgtg gctgaagagt tccttaagaa tttttaaacc atctggctgg 600 atctcgtggc cttccccctc agactaccca tgtctccacg aaggcgtcct ggagtcactc 660 cccgcgctgc tctacccacc cgcccctcgg ctcctcgcct tccccctccc gtccgccttc 720 tcccctccct cccgctcctg ggaaagagag aaaccaccgc tgcgggtggg tagagaagca 780 cttggcgcct cggggagggg accgcgcccg cctcatttgc gccttgcagc actgctggac 840 caggttacaa gatgttcacc taagattgag acctagtgac tacatttcct acgggaacaa 900 ataaatggtt tttcatctcc cggagataca ttacaaacaa atatggtgct aaaagaactc 960 cttacctttc tctgactaca atttatttgg acatactttt gtattgaaga gaggtataca 1020 tactgaagct acttgctgta ctataggaga ctctgtcctg taggatcatg gaccatccta 1080 gtagggaaaa ggatgaaaga caacggacaa ctaaacccat ggcacaaagg agtgcacact 1140 gctctcgacc atctggctcc tcatcgtcct ctggggttct tatggtggga cccaacttca 1200 gggttggcaa gaagatagga tgtgggaact tcggagagct cagattaggt aaaaatctct 1260 acaccaatga atatgtagca atcaaactgg aaccaataaa atcacgtgct ctacagcttc 1320 atttagagta cagattttat aaacagcttg gcagtgcagg tgaaggtctc ccacaggtgt 1380 attactttgg accatgtggg aaatataatg ccatggtgct ggagctcctt ggccctagct 1440 tggaggactt gtttgacctc tgtgaccgaa catttacttt gaagacggtg ttaatgatag 1500 ccatccagtt gctttctcga atggaatacg tgcactcaaa gaacctcatt taccgagatg 1560 tcaagccaga gaacttcctg attggtcgac aaggcaataa gaaagagcat gttatacaca 1620 ttatagactt tggactggcc aaggaataca ttgaccccga aaccaaaaaa cacatacctt 1680 atagggaaca caaaagttta actggaactg caagatatat gtctatcaac acgcatcttg 1740 gcaaagagca aagccggaga gatgatttgg aagccctagg ccatatgttc atgtatttcc 1800 ttcgaggcag cctcccctgg caaggactca aggctgacac attaaaagag agatatcaaa 1860 aaattggtga caccaaaagg aatactccca ttgaagctct ctgtgagaac tttccagagg 1920 agatggcaac ctaccttcga tatgtcaggc gactggactt ctttgaaaaa cctgattatg 1980 agtatttacg gaccctcttc acagacctct ttgaaaagaa aggctacacc tttgactatg 2040 cctatgattg ggttgggaga cctattccta ctccagtagg gtcagttcac gtagattctg 2100 gtgcatctgc aataactcga gaaagccaca cacataggga tcggccatca caacagcagc 2160 ctcttcgaaa tcagaatgta tcatcagagc gccgaggaga gtgggaaatt cagcccagcc 2220 ggcagaccaa tacctcatac ctaacgtctc acttggctgc agaccgccat gggggatcag 2280 tgcaggtggt tagctcaacc aatggagagc tgaatgttga tgatcccacg ggagcccact 2340 ccaatgcacc aatcacagct catgccgagg tggaggtagt ggaggaagct aagtgctgct 2400 gtttctttaa gaggaaaagg aagaagactg ctcagcgcca caagtgacca gtgcctccca 2460 ggagtcctca ggccctgggg actctgactc aattgtacct gcagctcctg ccatttctca 2520 ttggaaggga ctcctctttg ggggagggtg gatatccaaa ccaaaaagaa gaaaacagat 2580 gcccccagaa ggggccagtg cgggcagcca gggcctagtg ggtcattggc catctccgcc 2640 tgcctaaggc tctgagcagg tcccagagct gctgttcctc cactgcttgc ccatagggct 2700 gcctggttga ctctccttcc cattgtttac agtgaaggtg tcattcacaa aaactcaagg 2760 actgctattc tccttcttcc ccttagttta ctcctggttt ttaccccacc ctcaaccctc 2820 tccagcataa aacctagtga gctaaaggct ttgtctgcag aaggagatca agaggctggg 2880 ggtaaggcca agaaggtagg aggaaaatgg cagacctggg ctggagaaga accttctccg 2940 tatcccaggt gtgcctggca gtatggtttc ctcttcctct gtgcctgtgc agcattcatc 3000 ccagctggcc ttggggttca ggttccttct tccctccctc ctgtgaagtt acactgtagg 3060 acacaagctg tgagcaatct gcagtctact gtccctgtgt gttggcgttc ttagcttttt 3120 tgacaaactc ttttctccag gtagtaggac aatgaaaatt gttctaagca aaggaaagaa 3180 aactgacttt gttgcacttt tagttttttt aaaaaaaacc aaaacaaaac atggcagatg 3240 catattgtgt ctggttatat tgggggtttt acttttacct gttttgaggg ggatggggcc 3300 ggccaagcca ttcagagaga acatgggtcc agaggacatt ctcagtggaa agagtttgat 3360 ctgcagcacc cagaagagaa gccaactcgg tgtcattctg agtgaacact caggttggca 3420 agaaaacata cttgaatttt cattcatctt ctcagcagct gaagaatgtc cctaccagag 3480 catcttgacc taatcagctt acagtttgaa aacctagctc tccagaacat gagatgagcc 3540 agccgagcca gactgtgacc aggaaacagc tcatcccaga gaaggagatg cttaacaaaa 3600 aaaaattgaa attgtttccc atgctgccag ggacttccaa ctagatagcc atgtgacgtc 3660 ctggtgactt gggggaaaaa ttagtgatga aacagccacc accatattgc cattagtgga 3720 aaaaaagagg acagtgaacc tgccttccac ctgccagagg gacctcaggg tgtggcatta 3780 tagggccagg aaaagaaaat cggtgtatcc tatctgcccc aatagctgag ctgtagcatt 3840 tgggctggcc tgccttatca gaaaccaagc ttatgaagat cttctcccag caggtccata 3900 gcagtaggct taggatgcag tatatggggc cgcatttaaa aggagggaaa gattgtttgg 3960 tgctggaaca ttccagggaa aaggagactg gaatgaaagg tctgaaatta tcttctcaat 4020 tggactcctt ccagaaaggt ggccgtgcct ctaagcatgt ttttcccagt atgccctagg 4080 cctcccccca tggtgttttc atatgaggta ctactgtgaa ggatctggtt cctcattcac 4140 tgtttgacaa gtctttcatg tgtggagtta ctcttctcat gcccaatttt catttgagtt 4200 tagtggctta accaaacaat gactcctcat tccagcggtg acagaagaga aagggtcatt 4260 tacatcagga aagaggtctt gtatctggga gtagagagct aaccatggag cacagtggct 4320 ggtgggtgac ttagtctgat ggtttgtgga ccatagaagt cttcacctct ggtttgaggt 4380 gcagggctgt cttttgtact ggagggtgtg gggatatttt ctgatagttg ccatttcttg 4440 aaaaattccc ttgatgtacc ttacacagag cagaaataac attaacatgg atcagaggta 4500 ctgggcttca tctgttccat tggaccttgg ctagggaata tcatttcact ggcatcaaac 4560 ctgcttagct tatgaaaaga tggtaatatg tcatttctat aaatgtttct atatatgaaa 4620 cataaaagtg gcagggagat acaatatcac acccctttcc cccaaaggac tgtgaaaaat 4680 tgggggttta tggcccttgc caattcccta gtgggttaaa agcccctatt ccttaaaatt 4740 ttaacatcgg tttcctccaa tttgggggtt ttgggggatt tgtccaactt aacctggtta 4800 gggaaaagtt taacatggtc ccctcacccc cccctgtttg gagaaaagcc cctgtgcctc 4860 ccccaaaga 4869 36 4480 DNA Homo sapiens misc_feature Incyte ID No 55064363CB1 36 atgaagtggg taggggacac tggagtgggg ggaaacatcc ctccatcctt cactacccca 60 gggctctcct ccagaccggg tgctatggtg gcggatcgca gccgctggcc actcgcccag 120 gggaagggcg cgcaggcggg cacatggaga gcggcggtgg aatgctccgg ccggggcctc 180 ggggcggcga gcgagtcccc tcagtgcccg ccgccgccgg gggtggaggg cgcggccggg 240 ccggcggagc ccgacggggc ggcggagggc gcggcaggcg gcagcggcga gggcgagagt 300 gggggcgggc cgcggcgggc tctgcgggca gtatacgtgc gcagtgagag ctcccagggc 360 ggcgcggccg gcggcccgga ggctggggcg cggcagtgcc tgctgcgggc ctgcgaggcc 420 gagggcgctc acctcacctc cgtgcccttc ggggagctgg acttcgggga gacggccgtg 480 ctcgacgcct tctacgacgc agatgttgct gtggtagaca tgagcgatgt ctccagacag 540 ccttccctct tctaccatct tggagtccga gaaagctttg acatggccaa taatgtgatc 600 ttgtaccatg acaccgatgc cgacactgct ctctctttga aggacatggt aactcaaaaa 660 aacacagcat ccagtggaaa ttattatttc atcccataca tcgtgacacc gtgcactgat 720 tatttttgct gcgagagtga tgcccagaga cgagcctccg agtacatgca gcccaactgg 780 gacaacatcc tgggcccgct gtgcatgcct ttggtggaca ggttcattag cctccttaag 840 gacatccacg tgacctcatg tgtttattac aaagaaacct tgttaaatga catccggaaa 900 gccagagaga aataccaagg tgaggaactg gcgaaggagc tagctcggat caagctccgc 960 atggataata ctgaggttct gacctcagac atcatcatta acttactcct gtcctaccgt 1020 gatatccagg actatgatgc gatggtgaag ctggtggaaa cactggagat gctgcctacg 1080 tgtgatttgg ccgatcagca taacattaaa ttccactatg cgtttgcact gaataggaga 1140 aacagcacag gtgaccgtga gaaggctctg cagatcatgc tccaggttct gcagagctgt 1200 gatcacccgg gccccgacat gttctgcctg tgtgggagga tctacaagga catcttcttg 1260 gattcagact gcaaagatga caccagccgc gacagcgcca ttgagtggta tcgcaaaggg 1320 tttgaactcc agtcatccct ctattcggga attaatcttg cagttttgct gattgttgct 1380 ggacaacaat ttgaaacttc cttggaacta aggaaaatag gtgtccggct gaacagtttg 1440 ttgggaagaa aagggagctt ggagaaaatg aacaattact gggatgtggg tcagttcttc 1500 agcgtcagca tgctggccca tgatgtcggg aaagccgtcc aggcagcaga gaggttgttc 1560 aaactgaaac ctccagtctg gtacctgcga tcattagttc agaacttgtt actaattcgg 1620 cgcttcaaga aaaccattat tgaacactcg cccaggcaag agcggctgaa cttctggtta 1680 gatataattt ttgaggcaac aaatgaagtc actaatggac tcagatttcc agttctggtc 1740 atagagccaa ccaaagtgta ccagccttct tatgtttcca taaacaatga agccgaggag 1800 agaacagttt ctttatggca tgtctcaccc acagaaatga aacagatgca cgaatggaat 1860 tttacagcct cttccataaa gggaataagc ctatcaaagt ttgatgaaag gtgttgtttt 1920 ctttatgtcc atgataattc tgatgacttt caaatctact tttccaccga agagcagtgc 1980 agtagatttt tctctttggt caaagagatg ataaccaata cagcaggcag tacggtggag 2040 ctggagggag agaccgatgg agacaccttg gagtatgagt atgaccatga tgcaaatggt 2100 gagagagttg tcttggggaa aggcacgtat gggattgtgt atgctggccg agatctgagc 2160 aatcaagtgc gaatagccat caaagaaatc ccggagagag atagcaggta ttctcagcct 2220 ctgcacgagg agatagccct gcacaagtac cttaagcacc gcaatatcgt tcagtacctg 2280 ggctctgttt cagagaacgg ctacattaag atatttatgg agcaggtgcc tggaggaagc 2340 ctttctgctc ttctgcgatc caaatggggg ccgatgaagg aaccgacaat caagttttac 2400 accaaacaga tcctggaggg ccttaagtat cttcatgaaa accagatcgt gcacagagac 2460 ataaagggcg ataatgttct ggtgaacacc tacagcggag tggtgaaaat ctccgatttt 2520 ggaacctcga aacgtcttgc gggtgtgaac ccctgcacag agacttttac tggcaccctg 2580 cagtacatgg cacctgagat aattgaccaa gggcctcgcg gatatggtgc cccagccgat 2640 atctggtccc tgggctgcac catcattgag atggccacca gcaagcctcc gttccatgag 2700 cttggtgagc cgcaggcagc catgttcaaa gtgggcatgt ttaagatcca ccctgagatt 2760 ccagaagccc tttcagctga agcccgagcc ttcattttat cctgtttcga gcctgacccc 2820 cacaaacgtg ccaccactgc tgagctactg agagagggtt tcttaaggca ggtgaacaag 2880 ggcaagaaga accgaattgc cttcaagccc tcagaaggtc cccgcggtgt cgtcctggcc 2940 ctgcccacac agggagagcc catggccacc agcagcagcg agcacggctc tgtctcccca 3000 gactccgacg cccagcctga cgcactcttt gagaggaccc gggcgcccag gcaccacctt 3060 ggccacctcc tcagtgttcc agacgagagc tcagccttgg aagaccgggg cttggcctcg 3120 tccccggagg acagggacca gggcctcttc ctgctacgca aggacagtga gcgccgtgcc 3180 atcctgtaca aaatcctctg ggaggagcag aaccaggtgg cttccaacct gcaggagtgt 3240 gtggcccaga gttccgaaga gttgcatctc tcagttggac acatcaagca aatcattggg 3300 atcctgaggg acttcatccg ctccccagag caccgggtga tggcgaccac aatatcaaag 3360 ctcaaggtgg acctggactt tgacagctcg tccatcagtc agattcacct ggtgctgttc 3420 ggatttcagg atgccgtaaa taaaattttg aggaaccact taattaggcc ccactggatg 3480 ttcgcgatgg acaacatcat ccgccgagcg gtgcaggccg cggtcaccat tctcatccca 3540 gagctccgag cccactttga gcctacctgt gagactgaag gggtagataa ggacatggat 3600 gaagcggaag agggctatcc cccagccacc ggacctggcc aggaggccca gccccaccag 3660 cagcacctga gcctccagct gggtgagctc agacaggaga ccaacagact tttggaacac 3720 ctagttgaaa aagagagaga gtaccagaat cttctgcggc aaactctaga acagaaaact 3780 caagaattgt atcaccttca gttaaaatta aaatcgaatt gtattacaga gaacccagca 3840 ggcccctacg ggcagagaac agataaagag cttatagact ggttgcggct gcaaggagct 3900 gatgcaaaga caattgaaaa gattgttgaa gagggttata cactttcgga tattcttaat 3960 gagatcacta aggaagatct aagatacctt cgactacggg gtggtctcct ctgcagactc 4020 tggagtgcgg tctcccagta cagaagggct caggaggcct cagaaaccaa agacaaggct 4080 tgataccaat cagctaagct gtggcagagt gtcccaccac gctacatgtt ttgttaaagc 4140 ttctgttagt gtatacacga attccgctgt gtttacatat ttaaaaatgc cattgttcaa 4200 ttaatagttt aagaacttgt tttaaatact gtcctgagtt tcttttgaaa cctgttattt 4260 ataaacatag aactgtgtgt attgtgaaaa cagtgagcct tggttttgac ctcccggaat 4320 attaggaaat tcacttgtag tcccagctat gcaggaggct gaggtgggag gattgcttga 4380 gcccaggagg tgtggaggct gcagtgagcc atgatcacac cactgcactc cagcctgggc 4440 aacagagccc gacctgtctc aaaaaaaagt acacccttca 4480 37 4415 DNA Homo sapiens misc_feature Incyte ID No 7482044CB1 37 cgagacgtcc ccggcacgct gatggagccc gggcgcggcg cggggcccgc gggcatggcg 60 gagcctcggg cgaaggcggc gcggccgggg ccccagcgct ttctgcggcg cagcgtggta 120 gagtcggacc aggaggagcc gccgggcttg gaggcagccg aggcgccggg cccgcagccc 180 ccgcagcccc tgcagcgccg ggtgcttctg ctctgcaaga cgcgccgcct catcgcggag 240 cgcgcccgcg gacgccccgc cgcccccgcg cccgcagcgc tggtagcgca gccgggagcc 300 cccggagccc ccgcggacgc cggccccgag cccgtgggca cgcaggagcc cggcccggac 360 cccatcgcag ccgctgtcga aaccgcgcct gcccccgacg gcggccccag ggaggaggcg 420 gcggcgaccg tgaggaagga ggatgagggg gcggccgagg cgaagcctga gcccgggcgc 480 actcgccggg acgagcccga agaggaggag gacgacgagg acgacctcaa ggccgtggcc 540 acctctctgg acggccgctt cctcaagttc gacatcgagc tgggccgcgg ttccttcaag 600 acggtctaca aggggctgga cacggagacc tgggtggagg tggcctggtg tgagctgcag 660 gaccggaagc tcaccaagct ggagcggcag cggttcaagg aagaggctga gatgctgaaa 720 ggcctgcagc accccaacat cgtgcgcttc tacgacttct gggagtccag cgccaagggc 780 aagcggtgca ttgtgctggt gacggagctg atgacctcag ggacgctgaa gacatacctg 840 aagcggttca aggtgatgaa gcccaaggtt ctccgcagct ggtgccggca gatcctgaag 900 ggcctgctgt tcctgcacac aaggacgcca cccatcatcc accgagacct gaaatgtgac 960 aatattttca tcaccggacc aactgggtct gtgaagattg gcgacttggg cctggccact 1020 ctgaaaagag cgtcatttgc caaaagtgtg ataggtactc ccgagttcat ggcgcccgag 1080 atgtacgagg agcactacga tgagtccgtg gacgtctatg cctttgggat gtgcatgctg 1140 gagatggcca cctcggagta cccctactcg gagtgccaga atgcggccca gatctaccgc 1200 aaggtcacct gtggtatcaa gccggccagc tttgagaaag tgcacgatcc tgaaatcaag 1260 gagattattg gggagtgtat ctgcaaaaac aaggaggaaa ggtacgagat caaagacctg 1320 ctgagccacg ccttcttcgc agaggacaca ggcgtgaggg tggagctcgc ggaggaggac 1380 cacggcagga agtccaccat cgccctgagg ctctgggtgg aagaccccaa gaaactgaag 1440 ggaaagccca aggacaatgg agccatagag ttcaccttcg acctggagaa ggagacgccg 1500 gatgaggtgg cccaagagat gattgagtct ggattcttcc acgagagtga cgtcaagatc 1560 gtggccaagt ccatccgtga ccgcgtggcc ttgatccagt ggcggcggga gaggatctgg 1620 cccgcgctgc agcccaagga gcagcaggat gtgggcagcc cggacaaggc caggggtccg 1680 ccggtgcccc tgcaggtcca ggtgacctac catgcacagg ctgggcagcc cgggccacca 1740 gagcccgagg agccggaggc cgaccagcac ctcctgccac ctacgttgcc gaccagcgcc 1800 acctccctgg cctcggacag caccttcgac agcggccagg gctctaccgt gtactcagac 1860 tcgcagagca gccagcagag cgtgatgctt ggctcccttg ccgacgcagc gccgtccccg 1920 gcccagtgtg tgtgcagccc ccctgtgagc gaggggcccg tcctgccgca gagcctgccc 1980 tcgctggggg cctaccagca gcccacggct gcacctggct tgccggtggg ctctgtcccg 2040 gcccccgcct gccctccgtc cctccagcag cacttcccgg atccggccat gagcttcgcc 2100 cccgtgctgc cgccgcccag cacccccatg cccacgggcc caggccagcc agcacccccc 2160 ggccagcagc ctcctccgct ggcccagccg acacccctgc cgcaggtcct ggccccacag 2220 cccgtggtcc ccctccagcc ggttcccccc cacctgccac cgtacctggc tccagcctcc 2280 caggtggggg cccccgctca gctgaagccc ctccagatgc cacaggcgcc cctgcagccg 2340 cttgctcaag tccctccgca gatgcccccg attcctgttg tgccccccat cacgcccctg 2400 gcgggaatcg acggcctccc tccggccctc ccagacctgc cgaccgcgac tgtgcctccc 2460 atgccaccac ctcagtattt ctctccagcc gtgatcttgc cgagcctcgc tgccccactc 2520 ccccctgcgt ccccagcctt gcctctgcag gctgtgaagc tgccccaccc ccctggggcg 2580 cccctggcca tgccctgccg gaccattgtg ccaaatgcac cggccactat ccccctgctg 2640 gccgtagccc caccgggcgt ggctgccctg tccattcatt ctgccgtggc ccagctccca 2700 ggccaacctg tgtacccagc ggccttccca cagatggcgc ctactgacgt ccctccttcc 2760 ccccatcaca cggtgcagaa tatgagggcc acccctccac agccggcact gcctccacaa 2820 cccacactgc ccccacaacc cgtgctgccc ccgcaaccca cgctgccccc tcaacctgtg 2880 ttgcccccgc aacccacacg gccccctcaa cctgtgctgc ccccgcaacc catgctgccc 2940 ccacaacctg tgctgccccc gcagccggca ctgcctgtgc gccctgagcc cctccagccc 3000 caccttcctg aacaagctgc tccagctgct acaccaggga gccagattct gcttggccac 3060 ccagctccct atgctgtgga cgtcgccgct caggtcccca ccgtgcctgt gccaccggct 3120 gcggtcctct cgccgcctct gccggaagtg ctgctgcctg ccgcccctga gctcctgcct 3180 cagttcccca gctccctggc cacggtgtct gcctctgtgc agagtgtgcc cacccagact 3240 gccacacttc tgccaccagc aaacccaccg ctgcctggcg ggcccgggat cgccagccct 3300 tgcccaactg tccagctgac ggtggaacca gtccaagagg agcaggcctc acaggacaag 3360 ccgcccggcc tcccgcagag ctgtgagagc tatggaggtt ctgatgtcac ttctggaaaa 3420 gagctgagtg acagctgtga aggcgccttt ggagggggca ggctggaggg cagggcagcc 3480 cgaaaacacc accgcaggtc cacgcgtgcg cgctcccggc aggagagggc cagccggccc 3540 cggcttacca tcttgaacgt gtgcaacact ggggacaaga tggtggagtg ccagctggag 3600 acgcacaacc acaagatggt gaccttcaag ttcgacttgg acggggacgc acccgatgaa 3660 attgccacgt atatggtgga gcatgacttt atcctgcagg ccgagcggga aacgttcatc 3720 gagcagatga aggatgtcat ggacaaggca gaggacatgc tcagcgagga cacagacgcc 3780 gaccgtggct ccgacccagg gaccagcccg ccacacctca gcacctgcgg cctgggcacc 3840 ggggaggaga gccgacaatc ccaagccaac gcccccgtgt atcagcagaa cgtcctgcac 3900 accgggaaga ggtggttcat catctgtccg gtggctgagc accccgcccc cgaggcccct 3960 gaatcttcgc ccccacttcc tctaagctcc ctgccctgcc ctgccctgtt ccgcatgagc 4020 tgcgcctctg tgctcgcctg ccccctctct gcttgttagt tgctctttct ggctctgcct 4080 ctcctttgct ttcctcggga tgccactctg tgcccaggag ggtgcctgat ttcggggagt 4140 cctgacccga gcctgttgtc agagttggga ggggctctga gcagtgttgg gcaggccggg 4200 tctcccatcc cgaggccagc gttcctgtgc agagccccat ccactggttc ttgccctgag 4260 ccacatatgt ctgtgccatg ggctgagtgc cacgacaggc ccgtgtgaca gctgctgccc 4320 acgcatgtgg aagctaggtg ggactcattc ctaattctgc cgttgtaatg agacttgatt 4380 aaaacaccgc cacttttttg caaaaaaaaa aaaaa 4415 38 6306 DNA Homo sapiens misc_feature Incyte ID No 7476595CB1 38 agacacagaa acagatgaca gcagaaacac cagaaacaga tgacagcaga aacaccagaa 60 acagatgaca gcagaaacac cagaaacaga tgacagcaga aacaccagaa acagatgaca 120 gcagaaacac cagaaacaga tgacagcaga aacaccagaa acagatgaca gcagaaacac 180 cagaaacaga tgacagcaga aacaccagaa acagatgaat cagtgagtag ctctaatgcc 240 tccctgaaac ttcgaaggaa acctcgggaa agtgattttg aaacgattaa attgattagc 300 aatggagcct atggggcagt ctactttgtt cggcataaag aatcccggca gaggtttgcc 360 atgaagaaga ttaataaaca gaacctcatc cttcgaaacc agatccagca ggcctttgtg 420 gagcgggata tcctgacttt tgcagaaaac ccctttgttg tcagcatgta ttgctccttt 480 gaaacaaggc gccacttgtg catggtcatg gaatatgtgg aagggggaga ctgtgctact 540 ttaatgaaaa acatgggtcc tctccctgtt gatatggcca gaatgtactt tgctgagacg 600 gtcttggcct tggaatattt acataattat ggaattgtac acagggattt gaaaccagac 660 aacttgttgg ttacctccat ggggcacata aagctgacag attttggatt atctaaggtg 720 ggactaatga gcatgactac caacctttac gagggtcata ttgagaagga tgctagagag 780 ttcctggata aacaggtctg tggcacacct gaatacattg caccagaagt gattctgagg 840 cagggttatg gaaagccggt ggactggtgg gccatgggga ttatcctcta tgaatttctg 900 gttggatgcg tgccattctt tggggatact ccagaggagc tatttggaca agtcatcagt 960 gatgagatca actggcctga gaaggatgag gcacccccac ctgatgccca ggatctgatt 1020 accttactcc tcaggcagaa tcccctggag aggctgggaa caggtggtgc atatgaagtc 1080 aaacagcatc gattcttccg ttctttagac tggaacagtt tgctgagaca gaaggcagaa 1140 tttattcccc aactggaatc tgaggatgac acaagttatt ttgatactcg gtctgagaag 1200 tatcatcata tggaaacgga ggaagaagat gacacaaatg atgaagactt taatgtggaa 1260 ataaggcagt tttcttcatg ttcacacagg ttttcaaaac tttttctaaa tgattaccta 1320 gatgcacctg caaatgggcc agcactaccc tcctgtgtat gggaatggca tcgaggtaag 1380 gatttccctg gagaaggtgg tagccagtct gtcctagagc caggacagaa gcttgctaag 1440 tgtggactca gaccaggact gttctctggg ccatcaaaga caacaatgcc aacccctaaa 1500 cactgcttcc ttctttgcct tgatactgaa agcaacagac ataaactcag ttctggccta 1560 cttcccaaac tggctatttc aacagaggga gagcaagatg aagctgcctc ctgccctgga 1620 gacccccatg aggagccagg aaagccagcc cttcctcctg aagagtgtgc ccaggaggag 1680 cctgaggtca ccaccccagc cagcaccatc agcagctcca ccctgtcaga tatgtttgct 1740 gtttcccctc tgggaagtcc aatgtctccc cattccctgt cctcggaccc ttcttcttca 1800 cgagattcct ctcccagccg agattcctca gcagcttctg ccagtccaca tcagccgatt 1860 gtgatccaca gttcggggaa gaactacggc tttaccatcc gagccatccg ggtgtatgtg 1920 ggagacagtg acatctatac agtgcaccat atcgtctgga atgtagaaga aggaagtccg 1980 gcatgccagg caggactgaa ggctggagat cttatcactc acatcaatgg agaaccagtg 2040 catggacttg tccacacaga agttatagaa ctcctactga agagtgggaa taaggtgtca 2100 atcactacta ccccatttga aaacacatca atcaaaactg gaccagccag gagaaacagc 2160 tataagagcc ggatggtgag gcggagcaag aaatccaaga agaaagaaag tctcgaaagg 2220 aggagatctc ttttcaaaaa gctagccaag cagccttctc ctttactcca caccagccga 2280 agtttctcct gcttgaacag atccctgtca tcgggtgaga gcctcccagg ttcccccact 2340 catagcttgt ctccccggtc tccaacacca agctaccgct ccacccctga cttcccatct 2400 ggtactaatt cctcccagag cagctcccct agttctagtg cccccaattc cccagcaggg 2460 tccgggcaca tccggcccag cactctccac ggtcttgcac ccaaactcgg cgggcagcgg 2520 taccggtccg gaaggcgaaa gtccgccggc aacatcccac tgtccccgct ggcccggacg 2580 ccctctccaa ccccgcaacc cacctccccg cagcggtcac catcccctct tctgggacac 2640 tcactgggca attccaagat cgcgcaagcc tttcccagca agatgcactc cccgcccacc 2700 atcgtcagac acatcgtgag gcccaagagt gcggagcccc ccaggtcccc gctgctcaag 2760 cgcgtgcagt ccgaggagaa gctgtcgccc tcttacggca gtgacaagaa gcacctgtgc 2820 tcccgcaagc acagcctgga ggtgacccaa gaggaggtgc agcgggagca gtcccagcgg 2880 gaggcgccgc tgcagagcct ggatgagaac gtgtgcgacg tgccgccgct cagccgcgcc 2940 cggccagtgg agcaaggctg cctgaaacgc ccagtctccc ggaaggtggg ccgccaggag 3000 tctgtggacg acctggaccg cgacaagctg aaggccaagg tggtggtgaa gaaagcagac 3060 ggcttcccag agaaacagga atcccaccag aaatcccatg gacccgggag tgatttggaa 3120 aactttgctc tgtttaagct ggaagagaga gagaagaaag tctatccgaa ggctgtggaa 3180 aggtcaagta cttttgaaaa caaagcgtct atgcaggagg cgccaccgct gggcagcctg 3240 ctgaaggatg ctcttcacaa gcaggccagc gtgcgcgcca gcgagggtgc gatgtcggat 3300 ggccgggtgc ctgcggagca ccgccagggt ggcggggact tcagacgggc ccccgctcct 3360 ggcaccctcc aggatggtct ctgccactcc ctcgacaggg gcatctctgg gaagggggaa 3420 ggcacggaga agtcctccca ggccaaggag cttctccgat gtgaaaagtt agacagcaag 3480 ctggccaaca tcgattacct ccgaaagaaa atgtcacttg aggacaaaga ggacaacctc 3540 tgccctgtgc tgaagcccaa gatgacagct ggctcccacg aatgcctgcc agggaaccca 3600 gtccgaccca cgggtgggca gcaggagccc ccgccggctt ctgagagccg agcttttgtc 3660 agcagcaccc atgcagctca gatgagtgcc gtctcttttg ttcccctcaa ggccttaaca 3720 ggccgggtgg acagtggaac ggagaagcct ggcttggttg ctcctgagtc ccctgttagg 3780 aagagcccct ccgagtataa gctggaaggt aggtctgtct catgcctgaa gccgatcgag 3840 ggcactctgg acattgctct cctgtccgga cctcaggcct ccaagacaga actgccttcc 3900 ccagagtctg cacagagccc cagcccaagt ggtgacgtga gggcctctgt gccaccagtt 3960 ctccccagca gcagtgggaa aaagaacgat accaccagtg caagagagct ttctccttcc 4020 agcttaaaga tgaataaatc ctacctgctg gagccttggt tcctgccccc cagccgaggt 4080 ctccagaatt caccagcagt ttccctgcct gacccagagt tcaagaggga caggaaaggt 4140 ccccatccta ctgccaggag ccctggaaca gtcatggaaa gcaatcccca acagagagag 4200 ggcagctccc ctaaacacca agaccacacc actgacccca agcttctgac ctgcctgggg 4260 cagaacctcc acagccctga cctggccagg ccacgctgcc cgctcccacc tgaagcttcc 4320 ccctcaaggg agaagccagg cctgagggaa tcgtctgaaa gaggccctcc cacagccaga 4380 agcgagcgct ctgctgcgag ggctgacaca tgcagagagc cctccatgga actgtgcttt 4440 ccagaaactg cgaaaaccag tgacaactcc aaaaatctcc tctctgtggg aaggacccac 4500 ccagatttct atacacagac ccaggccatg gagaaagcat gggcgccggg tgggaaaacg 4560 aaccacaaag atggcccagg tgaggcgagg cccccgccca gagacaactc ctctctgcac 4620 tcagctggaa ttccctgtga gaaggagctg ggcaaggtga ggcgtggcgt ggaacccaag 4680 cccgaagcgc ttcttgccag gcggtctctg cagccacctg gaattgagag tgagaagagt 4740 gaaaagctct ccagtttccc atctttgcag aaagatggtg ccaaggaacc tgaaaggaag 4800 gagcagcctc tacaaaggca tcccagcagc atccctccgc cccctctgac ggccaaagac 4860 ctgtccagcc cggctgccag gcagcattgc agttccccaa gccacgcttc tggcagagag 4920 ccgggggcca agcccagcac tgcagagccc agctcgagcc cccaggaccc tcccaagcct 4980 gttgctgcgc acagtgaaag cagcagccac aagccccggc ctggccctga cccgggccct 5040 ccaaagacta agcaccccga ccggtccctc tcctctcaga aaccaagtgt cggggccaca 5100 aagggcaaag agcctgccac tcagtccctc ggtggctcta gcagagaggg gaagggccac 5160 agtaagagtg ggccggatgt gtttcctgct accccaggct cccagaacaa agccagcgat 5220 gggattggcc agggagaagg tgggccctct gtcccactgc acactgacag ggctcctcta 5280 gacgccaagc cacaacccac cagtggtggg cggcccctgg aggtgctgga gaagcctgtg 5340 catttgccaa ggccgggaca cccagggcct agtgagccag cggaccagaa actgtccgct 5400 gttggtgaaa agcaaaccct gtctccaaag caccccaaac catccactgt gaaagattgc 5460 cccaccctgt gcaaacagac agacaacaga cagacagaca aaagcccgag tcagccggcc 5520 gccaacaccg acagaagggc ggaagggaag aaatgcactg aagcacttta tgctccagca 5580 gagggcgaca agctcgaggc cggcctttcc tttgtgcata gcgagaaccg gttgaaaggc 5640 gcggagcggc cagccgcggg ggtggggaag ggcttccctg aggccagagg gaaagggccc 5700 ggtccccaga agccaccgac ggaggcagac aagcccaatg gcatgaaacg gtccccctca 5760 gccactgggc agagttcttt ccgatccacg gccctcccgg aaaagtctct gagctgctcc 5820 tccagcttcc ctgaaaccag ggccggagtt agagaggcct ctgcagccag cagcgacacc 5880 tcttctgcca aggccgccgg gggcatgctg gagcttccag cccccagcaa cagggaccat 5940 aggaaggctc agcctgccgg ggagggccga acccacatga caaagagtga ctccctgccc 6000 tccttccggg tctccaccct gcctctggag tcacaccacc ccgacccaaa caccatgggc 6060 ggggccagcc accgggacag ggctctctcg gtgactgcca ccgtagggga aaccaaaggg 6120 aaggaccctg ccccagccca gcctccccca gctaggaaac agaacgtggg cagagacgtg 6180 accaagccat ccccagcccc aaacactgac cgccccatct ctctttctaa tgagaaggac 6240 tttgtggtac ggcagaggcg ggggaaagag agtttgcgta gcagccctca caaaaaggcc 6300 ttgtaa 6306 39 7151 DNA Homo sapiens misc_feature Incyte ID No 71824382CB1 39 aatatacgac ttaattgtat tcttttaaaa atgcattaag tatatatttt atggtaattt 60 accctcaaaa tagatgtata tgggtgaaat tgaagacgct tcagttaagt gaggttactg 120 gtgtgttgga tgtttaattc agcaccagca ttgcatgaca gttgtttgaa taacaagtgg 180 tttattttta aaaccatacc ttttaaaatt taggttcaga taatagtaaa agtcatcata 240 ataatttaaa ggaaaaccag cagaaatcga agcaaacatg tctggagaag tgcgtttgag 300 gcagttggag cagtttattt tggacgggcc cgctcagacc aatgggcagt gcttcagtgt 360 ggagacatta ctggatatac tcatctgcct ttatgatgaa tgcaataatt ctccattgag 420 aagagagaag aacattctcg aatacctaga atgggctaaa ccatttactt ctaaagtgaa 480 acaaatgcga ttacatagag aagactttga aatattaaag gtgattggtc gaggagcttt 540 tggggaggtt gctgtagtaa aactaaaaaa tgcagataaa gtgtttgcca tgaaaatatt 600 gaataaatgg gaaatgctga aaagagctga gacagcatgt tttcgtgaag aaagggatgt 660 attagtgaat ggagacaata aatggattac aaccttgcac tatgctttcc aggatgacaa 720 taacttatac ctggttatgg attattatgt tggtggggat ttgcttactc tactcagcaa 780 atttgaagat agattgcctg aagatatggc tagattttac ttggctgaga tggtgatagc 840 aattgactca gttcatcagc tacattatgt acacagagac attaaacctg acaatatact 900 gatggatatg aatggacata ttcggttagc agattttggt tcttgtctga agctgatgga 960 agatggaacg gttcagtcct cagtggctgt aggaactcca gattatatct ctcctgaaat 1020 ccttcaagcc atggaagatg gaaaagggag atatggacct gaatgtgact ggtggtcttt 1080 gggggtctgt atgtatgaaa tgctttacgg agaaacacca ttttatgcag aatcgctggt 1140 ggagacatac ggaaaaatca tgaaccacaa agagaggttt cagtttccag cccaagtgac 1200 tgatgtgtct gaaaatgcta aggatcttat tcgaaggctc atttgtagca gagaacatcg 1260 acttggtcaa aatggaatag aagactttaa gaaacaccca tttttcagtg gaattgattg 1320 ggataatatt cggaactgtg aagcacctta tattccagaa gttagtagcc caacagatac 1380 atcgaatttt gatgtagatg atgattgttt aaaaaattct gaaacgatgc ccccaccaac 1440 acatactgca ttttctggcc accatctgcc atttgttggt tttacatata ctagtagctg 1500 tgtactttct gatcggagct gtttaagagt tacggctggt cccacctcac tggatcttga 1560 tgttaatgtt cagaggactc tagacaacaa cttagcaact gaagcttatg aaagaagaat 1620 taagcgcctt gagcaagaaa aacttgaact cagtagaaaa cttcaagagt caacacagac 1680 tgtccaagct ctgcagtatt caactgttga tggtccacta acagcaagca aagatttaga 1740 aataaaaaac ttaaaagaag aaattgaaaa actaagaaaa caagtaacag aatcaagtca 1800 tttggaacag caacttgaag aagctaatgc tgtgaggcaa gaactagatg atgcttttag 1860 acaaatcaag gcttatgaaa aacaaatcaa aacgttacaa caagaaagag aagatctaaa 1920 taaggaacta gtccaggcta gtgagcgatt aaaaaaccaa tccaaagagc tgaaagacgc 1980 acactgtcag aggaaactgg ccatgcagga attcatggag atcaatgagc ggctaacaga 2040 attgcacacc caaaaacaga aacttgctcg ccatgtccga gataaggaag aagaggtgga 2100 cctggtgatg caaaaagttg aaagcttaag gcaagaactg cgcagaacag aaagagccaa 2160 aaaagagctg gaagttcata cagaagctct agctgctgaa gcatctaaag acaggaagct 2220 acgtgaacag agtgagcact attctaagca actggaaaat gaattggagg gactgaagca 2280 aaaacaaatt agttactcac caggagtatg cagcatagaa catcagcaag agataaccaa 2340 actaaagact gatttggaaa agaaaagtat cttttatgaa gaagaattat ctaaaagaga 2400 aggaatacat gcaaatgaaa taaaaaatct taagaaagaa ctgcatgatt cagaaggtca 2460 gcaacttgct ctcaacaaag aaattatgat tttaaaagac aaattggaaa aaaccagaag 2520 agaaagtcaa agtgaaaggg aggaatttga aagtgagttc aaacaacaat atgaacgaga 2580 aaaagtgttg ttaactgaag aaaataaaaa gctgacgagt gaacttgata agcttactac 2640 tttgtatgag aacttaagta tacacaacca gcagttagaa gaagaggtta aagatctagc 2700 agacaagaaa gaatcagttg cacattggga agcccaaatc acagaaataa ttcagtgggt 2760 cagcgatgaa aaggatgcac gagggtatct tcaggcctta gcttctaaaa tgactgaaga 2820 attggaggca ttaagaaatt ccagcttggg tacacgagca acagatatgc cctggaaaat 2880 gcgtcgtttt gcgaaactgg atatgtcagc tagactggag ttgcagtcgg ctctggatgc 2940 agaaataaga gccaaacagg ccatccaaga agagttgaat aaagttaaag catctaatat 3000 cataacagaa tgtaaactaa aagattcaga gaagaagaac ttggaactac tctcagaaat 3060 cgaacagctg ataaaggaca ctgaagagct tagatctgaa aagggtatag agcaccaaga 3120 ctcacagcat tctttcttgg catttttgaa tacgcctacc gatgctctgg atcaatttga 3180 agattccttt tcttcttcct catcttcact gattgatttt ttggatgaca ctgatcccgt 3240 tgagaacaca tatgtatgga acccgagcgt caagtttcac atccagtcac ggtccacatc 3300 tccttccaca tctagtgaag ctgagccagt taagactgta gactccactc cactttcagt 3360 tcacacacca accttaagga aaaaaggatg tcctggttca actggctttc cacctaagcg 3420 caagactcac cagttttttg taaaatcttt tactactcct accaagtgtc atcagtgtac 3480 ctccttgatg gtgggtttaa taagacaggg ctgttcatgt gaagtgtgtg gattctcatg 3540 ccatataact tgtgtaaaca aagctccaac cacttgtcca gttcctcctg aacagacaaa 3600 aggtcccctg ggtatagatc ctcagaaagg aataggaaca gcatatgaag gtcatgtcag 3660 gattcctaag ccagctggag tgaagaaagg gtggcagaga gcactggcta tagtgtgtga 3720 cttcaaactc tttctgtacg atattgctga aggaaaagca tctcagccca gtgttgtcat 3780 tagtcaagtg attgacatga gggatgaaga attttctgtg agttcagtct tggcttctga 3840 tgttatccat gcaagtcgga aagatatacc ctgtatattt agggtcacag cttcccagct 3900 ctcagcatct aataacaaat gttcaatcct gatgctagca gacactgaga atgagaagaa 3960 taagtgggtg ggagtgctga gtgaattgca caagattttg aagaaaaaca aattcagaga 4020 ccgctcagtc tatgttccca aagaggctta tgacagcact ctacccctca ttaaaacaac 4080 ccaggcagcc gcaatcatag atcatgaaag aattgctttg ggaaacgaag aagggttatt 4140 tgttgtacat gtcaccaaag atgaaattat tagagttggt gacaataaga agattcatca 4200 gattgaactc attccaaatg atcagcttgt tgctgtgatc tcaggacgaa atcgtcatgt 4260 acgacttttt cctatgtcag cattggatgg gcgagagacc gatttttaca agctgtcaga 4320 aactaaaggg tgtcaaaccg taacttctgg aaaggtgcgc catggagctc tcacatgcct 4380 gtgtgtggct atgaaaaggc aggtcctctg ttatgaacta tttcagagca agacccgtca 4440 cagaaaattt aaagaaattc aagtcccata taatgtccag tggatggcaa tcttcagtga 4500 acaactctgt gtgggattcc agtcaggatt tctaagatac cccttgaatg gagaaggaaa 4560 tccatacagt atgctccatt caaatgacca tacactatca tttattgcac atcaaccaat 4620 ggatgctatc tgcgcagttg agatctccag taaagaatat ctgctgtgtt ttaacagcat 4680 tgggatatac actgactgcc agggccgaag atctagacaa caggaattga tgtggccagc 4740 aaatccttcc tcttgttgtt acaatgcacc atatctctcg gtgtacagtg aaaatgcagt 4800 tgatatcttt gatgtgaact ccatggaatg gattcagact cttcctctca aaaaggttcg 4860 acccttaaac aatgaaggat cattaaatct tttagggttg gagaccatta gattaatata 4920 tttcaaaaat aagatggcag aaggggacga actggtagta cctgaaacat cagataatag 4980 tcggaaacaa atggttagaa acattaacaa taagcggcgt tattccttca gagtcccaga 5040 agaggaaagg atgcagcaga ggagggaaat gctacgagat ccagaaatga gaaataaatt 5100 aatttctaat ccaactaatt ttaatcacat agcacacatg ggtcctggag atggaataca 5160 gatcctgaaa gatctgccca tgaaccctcg gcctcaggaa agtcggacag tattcagtgg 5220 ctcagtcagt attccatcta tcaccaaatc ccgccctgag ccaggccgct ccatgagtgc 5280 tagcagtggc ttgtcagcaa ggtcatccgc acagaatggc agcgcattaa agagggaatt 5340 ctctggagga agctacagtg ccaagcggca gcccatgccc tccccgtcag agggctcttt 5400 gtcctccgga ggcatggacc aaggaagtga tgccccagcg agggactttg acggagagga 5460 ctctgactct ccgaggcatt ccacagcttc caacagttcc aacctaagca gccccccaag 5520 cccagtttca ccccgaaaaa ccaagagcct ctccctggag agcactgacc gcgggagctg 5580 ggacccgtga gctgcctcag cactgggacc tctcgctctc cgctccctgc cactcgcctc 5640 ctctcacttt catctcttcc ctccacctcg cctgctcggc ctgaaagcca ccaggggctg 5700 gcagcagtag caggacaggg cttcaggagt tctgacgaca cgactctcag atccacgccc 5760 ccagcctaac agcaacaaca aagacagact ttccgtagca gcttagatta acgttgattt 5820 cattccatgc acttagagtt gctttcagta acattttacc cctactccca aaggtagctt 5880 aaatagacag attacacaaa tgtaagtgat aagaataaga ttagacagat tttgctttca 5940 cagtagagtc tcattatagt cctaaaatag ctcatgggct tctccgcatc cagaagggag 6000 aattggtccc tggagtggct cactaagctc ttaatcagca aacgcagtga gtatcaacct 6060 gattgttgcc aggaaatcct tatgaattaa aacaatgcat attttactac agtacagagt 6120 ttaaatgaat acataaatgt agaagtactg aatgtatata tttaaaagga gcctcttgta 6180 ttcaacaaaa gatggatgca tatataagag agatgattta atttaaagaa atatgttgtt 6240 tcttgtctgt aatgtaatgt aaagggtgga aaggcctcaa gctcacattt gtagagagag 6300 agcgagagaa atcagagttc cctttattgc cctgtcctca aactggtcat aggctctagt 6360 cacctgggga gctgtagaaa acacttgcag agccaggttt tgctggtttg gggcatgccc 6420 tgggcaccag agctttaaca tttgaagcca cttcagcagc agcagcaaaa ggcgaactca 6480 tctctaccca agatgtttct tttcctagtg gtggaatttg aacacttctc actttttatt 6540 gtattttatc ttccgcagat aaatgtagaa atacacggtt ctgtcacctc tgatcccttc 6600 catctgaaag ggtacaagga gtgttgtagc ttctgaaggt gcagaaaaca atttctaaaa 6660 atgcttttat tcctgggcta atcctgtccc tccctaagtc gcagcgaggt gtctgtccca 6720 gggctggaga tgcttcccaa ggaggagtct gttttgttga gagtgggcgt gggcttcttc 6780 acataagcct ggggaaggaa gaaaaaacgg ctttcattac caaataatgt aaaacctcaa 6840 aagcaagggc ttcaacagcc ttaaccaaat attattcccc atagccagtg gaaaatggat 6900 gtgacaaccc cagtgcgcag gccagagtga gtgagcccag cacggcgctc cgactggctt 6960 cctctctcag gtgctggatt gtggggttag tggcatttcc agctggattc ctcctgttgt 7020 agttgccata aggaaatgag atgcagaatc agaaggatct atttctacag aatcatttca 7080 ccagttaagc acatgagtag agaaagagat aaaaataaaa gtatctcatg aaggaaagaa 7140 aaaaaaaaaa a 7151 40 2378 DNA Homo sapiens misc_feature Incyte ID No 3566882CB1 40 aggcagcagc cacagcgggg agtgcgcggc gcggggacag gaagagaggg gcaatggctg 60 ccgaccccac cgagctgcgg ctgggcagcc tccccgtctt cacccgcgac gacttcgagg 120 gcgactggcg cctagtggcc agcggcggct tcagccaggt gttccaggcg cggcacaggc 180 gctggcggac ggagtacgcc atcaagtgcg ccccctgcct tccacccgac gccgccagga 240 cctttgcagc ttctgtttcc ccactcccct ctatttacct agcgaagatt tcagacttcg 300 gcctgtccaa gtggatggaa cagtccaccc ggatgcagta catcgagagg tcggctctgc 360 ggggcatgct cagctacatc ccccctgaga tgttcctgga gagtaacaag gccccaggac 420 ctaaatatga tgtgtacagc cccccgaccc tgccaccccg ggctggggtg atcttggatg 480 ttcaactaag tcattcagaa agggttctct gcatccacag ctttgcaatt gtcatctggg 540 agctactcac tcagaagaaa ccatactcag agctcacgtc acagctaaag gaaaggaaag 600 ggttcaacat gatgatgatt attatccgag tgacggcagg catgcggccc tccctacagc 660 ctgtctctga ccaatggcca agcgaggccc agcagatggt ggacctgatg aaacgctgct 720 gggaccagga ccccaagaag aggccatgct ttctagacat taccatcgag acagacatac 780 tgctgtcact gctgcagagt cgtgtggcag tcccagagag caaggccctg gccaggaagg 840 tgtcctgcaa gctgtcgctg cgccagcccg gggaggttaa tgaggacatc agccaggaac 900 tgatggacag tgactcagga aactacctga agcgggccct tcagctctcc gaccgtaaga 960 atttggtccc gagagatgag gaactgtgta tctatgagaa caaggtcacc cccctccact 1020 tcctggtggc ccagggcagt gtggagcagg tgaggttgct gctggcccac gaggtagacg 1080 tggactgcca gacggcctct ggatacacgc ccctcctgat cgccgcccag gaccagcaac 1140 ccgacctctg tgccctgctt ttggcacatg gtgctgatgc caaccgagtg gatgaggatg 1200 gctgggcccc actgcacttt gcagcccaga atggggatga cggcactgcg cgcctgctcc 1260 tggaccacgg ggcctgtgtg gatgcccagg aacgtgaagg gtggacccct cttcacctgg 1320 ctgcacagaa taactttgag aatgtggcac ggcttctggt ctcccgtcag gctgacccca 1380 acctgcatga ggctgagggc aagacccccc tccatgtggc cgcctacttt ggccatgtta 1440 gcctggtcaa gctgctgacc agccaggggg ctgagttgga tgctcagcag agaaacctga 1500 gaacaccact gcacctggca gtagagcggg gcaaagtgag ggccatccaa cacctgctga 1560 agagtggagc ggtccctgat gcccttgacc agagcggcta tggcccactg cacactgcag 1620 ctgccagggg caaatacctg atctgcaaga tgctgctcag gtacggagcc agccttgagc 1680 tgcccaccca ccagggctgg acacccctgc atctagcagc ctacaagggc cacctggaga 1740 tcatccatct gctggcagag agccacgcaa acatgggtgc tcttggagct gtgaactgga 1800 ctcccctgca cctagctgca cgccacgggg aggaggcggt ggtgtcagca ctgctgcagt 1860 gtggggctga ccccaatgct gcagagcagt caggctggac acccctccac ctggcggtcc 1920 agaggagcac cttcctgagt gtcatcaacc tcctagaaca tcacgcaaat gtccacgccc 1980 gcaacaaggt gggctggaca cccgcccacc tggccgccct caagggcaac acagccatcc 2040 tcaaagtgct ggtcgaggca ggcgcccagc tggacgtcca ggatggagtg agctgcacac 2100 ccctgcaact ggccctccgc agccgaaagc agggcatcat gtccttccta gagggcaagg 2160 agccgtcagt ggccactctg ggtggttcta agccaggagc cgagatggaa atttagacaa 2220 cttggccagc cgtggtggct cacgtctgta atcccagcac tttgggaggc tgaggcaggc 2280 agatcacctg agatcaagag tttgaggcca gcctggccaa catggcaaaa ccctgtctct 2340 gctaaaaata caaaatttag ctgggaaaaa aaaaaaaa 2378 

What is claimed is:
 1. An isolated polypeptide selected from the group consisting of: a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-20.
 2. An isolated polypeptide of claim 1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20.
 3. An isolated polynucleotide encoding a polypeptide of claim
 1. 4. An isolated polynucleotide encoding a polypeptide of claim
 2. 5. An isolated polynucleotide of claim 4 comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40.
 6. A recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide of claim
 3. 7. A cell transformed with a recombinant polynucleotide of claim
 6. 8. A transgenic organism comprising a recombinant polynucleotide of claim
 6. 9. A method of producing a polypeptide of claim 1, the method comprising: a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide, and said recombinant polynucleotide comprises a promoter sequence operably linked to a polynucleotide encoding the polypeptide of claim 1, and b) recovering the polypeptide so expressed.
 10. A method of claim 9, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-20.
 11. An isolated antibody which specifically binds to a polypeptide of claim
 1. 12. An isolated polynucleotide selected from the group consisting of: a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:21-40, c) a polynucleotide complementary to a polynucleotide of a), d) a polynucleotide complementary to a polynucleotide of b), and e) an RNA equivalent of a)-d).
 13. An isolated polynucleotide comprising at least 60 contiguous nucleotides of a polynucleotide of claim
 12. 14. A method of detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 12, the method comprising: a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex, and, optionally, if present, the amount thereof.
 15. A method of claim 14, wherein the probe comprises at least 60 contiguous nucleotides.
 16. A method of detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 12, the method comprising: a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof, and, optionally, if present, the amount thereof.
 17. A composition comprising a polypeptide of claim 1 and a pharmaceutically acceptable excipient.
 18. A composition of claim 17, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-20.
 19. A method for treating a disease or condition associated with decreased expression of functional KAP, comprising administering to a patient in need of such treatment the composition of claim
 17. 20. A method of screening a compound for effectiveness as an agonist of a polypeptide of claim 1, the method comprising: a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting agonist activity in the sample.
 21. A composition comprising an agonist compound identified by a method of claim 20 and a pharmaceutically acceptable excipient.
 22. A method for treating a disease or condition associated with decreased expression of functional KAP, comprising administering to a patient in need of such treatment a composition of claim
 21. 23. A method of screening a compound for effectiveness as an antagonist of a polypeptide of claim 1, the method comprising: a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting antagonist activity in the sample.
 24. A composition comprising an antagonist compound identified by a method of claim 23 and a pharmaceutically acceptable excipient.
 25. A method for treating a disease or condition associated with overexpression of functional KAP, comprising administering to a patient in need of such treatment a composition of claim
 24. 26. A method of screening for a compound that specifically binds to the polypeptide of claim 1, the method comprising: a) combining the polypeptide of claim 1 with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide of claim 1 to the test compound, thereby identifying a compound that specifically binds to the polypeptide of claim
 1. 27. A method of screening for a compound that modulates the activity of the polypeptide of claim 1, the method comprising: a) combining the polypeptide of claim 1 with at least one test compound under conditions permissive for the activity of the polypeptide of claim 1, b) assessing the activity of the polypeptide of claim 1 in the presence of the test compound, and c) comparing the activity of the polypeptide of claim 1 in the presence of the test compound with the activity of the polypeptide of claim 1 in the absence of the test compound, wherein a change in the activity of the polypeptide of claim 1 in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide of claim
 1. 28. A method of screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a sequence of claim 5, the method comprising: a) exposing a sample comprising the target polynucleotide to a compound, under conditions suitable for the expression of the target polynucleotide, b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound.
 29. A method of assessing toxicity of a test compound, the method comprising: a) treating a biological sample containing nucleic acids with the test compound, b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide of claim 12 under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide comprising a polynucleotide sequence of a polynucleotide of claim 12 or fragment thereof, c) quantifying the amount of hybridization complex, and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound.
 30. A diagnostic test for a condition or disease associated with the expression of KAP in a biological sample, the method comprising: a) combining the biological sample with an antibody of claim 11, under conditions suitable for the antibody to bind the polypeptide and form an antibody:polypeptide complex, and b) detecting the complex, wherein the presence of the complex correlates with the presence of the polypeptide in the biological sample.
 31. The antibody of claim 11, wherein the antibody is: a) a chimeric antibody, b) a single chain antibody, c) a Fab fragment, d) a F(ab′)₂ fragment, or e) a humanized antibody.
 32. A composition comprising an antibody of claim 11 and an acceptable excipient.
 33. A method of diagnosing a condition or disease associated with the expression of KAP in a subject, comprising administering to said subject an effective amount of the composition of claim
 32. 34. A composition of claim 32, wherein the antibody is labeled.
 35. A method of diagnosing a condition or disease associated with the expression of KAP in a subject, comprising administering to said subject an effective amount of the composition of claim
 34. 36. A method of preparing a polyclonal antibody with the specificity of the antibody of claim 11, the method comprising: a) immunizing an animal with a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, or an immunogenic fragment thereof, under conditions to elicit an antibody response, b) isolating antibodies from said animal, and c) screening the isolated antibodies with the polypeptide, thereby identifying a polyclonal antibody which binds specifically to a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20.
 37. A polyclonal antibody produced by a method of claim
 36. 38. A composition comprising the polyclonal antibody of claim 37 and a suitable carrier.
 39. A method of making a monoclonal antibody with the specificity of the antibody of claim 11, the method comprising: a) immunizing an animal with a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NO:1-20, or an immunogenic fragment thereof, under conditions to elicit an antibody response, b) isolating antibody producing cells from the animal, c) fusing the antibody producing cells with immortalized cells to form monoclonal antibody-producing hybridoma cells, d) culturing the hybridoma cells, and e) isolating from the culture monoclonal antibody which binds specifically to a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20.
 40. A monoclonal antibody produced by a method of claim
 39. 41. A composition comprising the monoclonal antibody of claim 40 and a suitable carrier.
 42. The antibody of claim 11, wherein the antibody is produced by screening a Fab expression library.
 43. The antibody of claim 11, wherein the antibody is produced by screening a recombinant immunoglobulin library.
 44. A method of detecting a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20 in a sample, the method comprising: a) incubating the antibody of claim 11 with a sample under conditions to allow specific binding of the antibody and the polypeptide, and b) detecting specific binding, wherein specific binding indicates the presence of a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20 in the sample.
 45. A method of purifying a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20 from a sample, the method comprising: a) incubating the antibody of claim 11 with a sample under conditions to allow specific binding of the antibody and the polypeptide, and b) separating the antibody from the sample and obtaining the purified polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-20.
 46. A microarray wherein at least one element of the microarray is a polynucleotide of claim
 13. 47. A method of generating an expression profile of a sample which contains polynucleotides, the method comprising: a) labeling the polynucleotides of the sample, b) contacting the elements of the microarray of claim 46 with the labeled polynucleotides of the sample under conditions suitable for the formation of a hybridization complex, and c) quantifying the expression of the polynucleotides in the sample.
 48. An array comprising different nucleotide molecules affixed in distinct physical locations on a solid substrate, wherein at least one of said nucleotide molecules comprises a first oligonucleotide or polynucleotide sequence specifically hybridizable with at least 30 contiguous nucleotides of a target polynucleotide, and wherein said target polynucleotide is a polynucleotide of claim
 12. 49. An array of claim 48, wherein said first oligonucleotide or polynucleotide sequence is completely complementary to at least 30 contiguous nucleotides of said target polynucleotide.
 50. An array of claim 48, wherein said first oligonucleotide or polynucleotide sequence is completely complementary to at least 60 contiguous nucleotides of said target polynucleotide.
 51. An array of claim 48, wherein said first oligonucleotide or polynucleotide sequence is completely complementary to said target polynucleotide.
 52. An array of claim 48, which is a microarray.
 53. An array of claim 48, further comprising said target polynucleotide hybridized to a nucleotide molecule comprising said first oligonucleotide or polynucleotide sequence.
 54. An array of claim 48, wherein a linker joins at least one of said nucleotide molecules to said solid substrate.
 55. An array of claim 48, wherein each distinct physical location on the substrate contains multiple nucleotide molecules, and the multiple nucleotide molecules at any single distinct physical location have the same sequence, and each distinct physical location on the substrate contains nucleotide molecules having a sequence which differs from the sequence of nucleotide molecules at another distinct physical location on the substrate.
 56. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:1.
 57. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:2.
 58. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:3.
 59. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:4.
 60. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:5.
 61. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:6.
 62. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:7.
 63. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:8.
 64. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:9.
 65. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:10.
 66. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:11.
 67. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:12.
 68. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:13.
 69. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:14.
 70. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:15.
 71. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:16.
 72. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:17.
 73. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:18.
 74. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:19.
 75. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID NO:20.
 76. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:21.
 77. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:22.
 78. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:23.
 79. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:24.
 80. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:25.
 81. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:26.
 82. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:27.
 83. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:28.
 84. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:29.
 85. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:30.
 86. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:31.
 87. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:32.
 88. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:33.
 89. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:34.
 90. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:35.
 91. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:36.
 92. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:37.
 93. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:38.
 94. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:39.
 95. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID NO:40. 